J 1365-2796 2005 01553

Journal of Internal Medicine 2005; 258: 301327
doi:10.1111/j.1365-2796.2005.01553.x
REVIEW
Brain regulation of food intake and appetite: molecules and networks

C. BROBERGER
From the Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Abstract. Broberger C (Karolinska Institute, Stockholm, Sweden). Brain regulation of food intake and appetite: molecules and networks (Review). J Intern Med 2005; 258: 301327. In the clinic, obesity and anorexia constitute prevalent problems whose manifestations are encountered in virtually every eld of medicine. However, as the command centre for regulating food intake and energy metabolism is located in the brain, the basic neuroscientist sees in the same disorders malfunctions of a model network for how integration of diverse sensory inputs leads to a coordinated behavioural, endocrine and autonomic response. The two approaches are not mutually exclusive; rather, much can be gained by combining both perspectives to understand the pathophysiology of over- and underweight. The present review summarizes recent advances in this eld including the characterization of peripheral metabolic signals
to the brain such as leptin, insulin, peptide YY, ghrelin and lipid mediators as well as the vagus nerve; signalling of the metabolic sensors in the brainstem and hypothalamus via, e.g. neuropeptide Y and melanocortin peptides; integration and coordination of brain-mediated responses to nutritional challenges; the organization of food intake in simple model organisms; the mechanisms underlying food reward and processing of the sensory and metabolic properties of food in the cerebral cortex; and the development of the central metabolic system, as well as its pathological regulation in cancer and infections. Finally, recent ndings on the genetics of human obesity are summarized, as well as the potential for novel treatments of body weight disorders. Keywords: brainstem, cerebral cortex, hypothalamus, metabolic, reward. feeding,
Introduction
Few tasks executed by the brain hold greater survival value than keeping us fed and in adequate nutritional state. It is not surprising then that the
This paper builds partly on presentations made at a Nobel Conference on Brain Control of Feeding Behaviour organized at the Karolinska Institute, Stockholm, Sweden, in September 911, 2004.
2005 Blackwell Publishing Ltd
central nervous system has developed a meticulously interconnected circuitry to meet this challenge. A consequence of this organization is that an energy-dense environment favours the development of obesity, whilst overcompensation may shut down the drive to feed. In todays society where evolving disease demographics and lifestyle allow for a greater diversity of metabolic phenotypes than perhaps ever before [1] disorders of both extremes of energy intake are common in health care. 301
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Obesity is increasing at an alarming rate in industrialized and developing countries alike [2] and is associated with a wealth of conditions aficting virtually all organ systems [3, 4]. Examples diverge widely to include cholelithiasis [5], osteoarthritis [6], infertility [7], stroke [8], cutaneous infections [9], wound healing deciencies [10], as well as a general increase in mortality [11] and social and professional stigmatization [12]. The urgency of the problem is illustrated dramatically by the previous rarity of paediatric obesityassociated type 2 diabetes, which is increasing to the point of taking over as the leading cause of childhood diabetes [13]. The opposite extreme of anorexia and hypophagia includes not only anorexia nervosa [14] but is also a common and potentially fatal complication of infections [15], malignancies [16] and ageing [17]. Unlike many other common diseases, these disorders have an obvious solution: adjusting food intake and exercise until normal body weight has been restored. However, it is no great revelation that this solution is as simple as it has repeatedly proved elusive [18]. Experimental studies conrm the common knowledge that weight loss almost always is followed by a rapid return to initial weight once the anorexigenic regimen is terminated [19]. Notably, the same applies to humans subjected to voluntary overfeeding [20], supporting the concept of a tightly regulated set-point for body weight. Treatment of eating disorders has been remarkably unsuccessful a consequence possibly of that we are battling ancient systems maintained by thrifty genes that favour the preservation of energy stores [21]. Available options for pharmacological therapy leave much to be desired, and compounds that have been introduced for obesity management have subsequently often been withdrawn due to intolerable side-effects [22]. The most effective obesity treatment at present is bariatric surgery, but this is a complicated procedure not without adverse effects [23]. Preventive measures have frustratingly limited effect. It has proved even more difcult to devise strategies for increasing food intake in cases of anorexia. Although some success has been reported with behavioural approaches for anorexia nervosa [24], the more common forms of cancerand inammation-associated anorexia remain a major therapeutic challenge. Novel treatments are greatly needed.
But what systems should such treatments target? Early clinical observations that patients with pituitary tumours and accompanying injury to the base of the brain develop obesity [2528], inspired experimental lesion studies [2933], which demonstrated that damage to particular regions of the hypothalamus and brainstem lead to profound, often fatal, alterations of feeding behaviour. It also became apparent that signals from the peripheral energy stores [34] and gastrointestinal canal [35] provide essential cues for appetite and satiety. Based on these and other ndings, Stellar [36] half a century ago proposed a dual centre hypothesis for the initiation of motivated behaviour. The hypothesis included both mechanisms for sensing peripheral cues, separate nuclei (i.e. the dual centres) for stimulating and inhibiting behaviour, and connections between the hypothalamus and higher brain regions to allow for internal states to determine the threshold for initiating behaviour. Of all motivated behaviours, the model is perhaps most applicable for food intake. Yet, for all its heuristic value, the dual centre hypothesis was as low on specics as it was laden with theory. Research dating in particular from the last decade has changed this. Today, we have an understanding of the circuitry and neuropharmacology of feeding behaviour that can be probed for therapeutic targets. The present article is not an exhaustive review of the central control of energy metabolism [37, 38], but summarizes recent advances, which have brought new insight into the peripheral signals describing the metabolic state to the brain; the input stations in the hypothalamus and brainstem sensitive to these signals, the organization of feeding behaviour in simple and complex organisms; the link between food intake and energy expenditure; the neural framework for integrating metabolic cues and reward properties; the mechanisms of infection- and cancer-associated anorexia; developmental and genetic causes of obesity and novel therapeutic strategies.
A central framework for sensing and orchestrating energy metabolism

The regulation of energy metabolism presents a prototypical homeostatic system, with the brain acting as the central coordinator and rectier (Fig. 1). It is one of the great wonders of the brain that body weight stays remarkably xed (as a
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
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Fig. 1 The central metabolic circuitry is regulated by numerous endocrine and neural inputs. Schematic illustration of how brain networks regulating ingestive behaviour communicate with peripheral organs. Hormones supplying information about the peripheral metabolic state to the brain include the gastrointestinal peptides ghrelin and PYY(3-36), insulin from the pancreas and leptin from adipose tissue. Ghrelin and leptin act both on the hypothalamus (Arc) and the brainstem (nTS). The afferent portion of the vagus nerve innervates most of the gastrointestinal tract where it collects information about the immediate alimentary state, and terminates in the nTS. The lipid mediator OEA is produced in the duodenum and activates the brainstem, possibly via the vagus nerve. Both the Arc (via antagonistic NPY- and POMC-expressing cells) and the nTS project further into the brain in parallel pathways to engage higher brain regions into ingestive behaviour. Outputs from the brain regulating energy expenditure include both branches of the autonomic nervous system; the sympathetic system whose preganglionic neurones are located in the intermediolateral cell column (IML), which is directly innervated by POMC neurones from the Arc, as well as the parasympathetic system with preganglionic neurones for the efferent portion of the vagus nerve located in the dorsal motor nucleus of the vagus (DMX). The efferent autonomic innervation regulates, e.g. glucose homeostasis via actions in liver and skeletal muscle. See text for details.
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the individual, which it does through two main channels. First, hormonal signals reecting the availability and demand for metabolic fuel is relayed via neurones in the hypothalamus. The receptors for these signals are primarily expressed on two neurochemically distinct sets of neurones located in the arcuate nucleus (Arc) in the mediobasal hypothalamus, alongside the third ventricle [40]. One neurone group expresses neuropeptide Y (NPY); increasing NPY release or activation of these neurones by a variety of approaches results in increased food intake and decreased energy expenditure. The other group expresses the neuropeptide precursor proopiomelanocortin (POMC), which is processed to melanocortin peptides; activation of these neurones has the opposite effect of triggering the NPY cells, i.e. decreased food intake and increased energy expenditure. The yinyang relationship between the two Arc groups is further underscored by their opposite regulation by leptin and insulin, hormones signalling metabolic afuence, which decrease the expression of NPY, whilst they increase the expression of POMC. The second main input for information pertaining to energy balance is the brainstem, classically viewed as a channel for visceroceptive information as cranial nerves, in particular the vagus nerve, carrying information from the alimentary organs enter the brain here. Vagal afferents synapse onto [41, 42] and excite [43] neurones in the brainstem nucleus tractus solitarii (nTS). From both the hypothalamus and the brainstem, projections fan further into the brain to engage other brain regions in the initiation and organization of food intake. As in all homeostatic systems, the brain has at its disposal three effector pathways to activate when the controlled variable (i.e. body weight) needs to be adjusted: behaviour (i.e. food intake), the endocrine system and the autonomic nervous system [44]. Importantly, all three of these systems are engaged downstream of the Arc and nTS stations to provide a synchronized response to uctuations in energy balance; the rst primarily in the volitional control of intake, the latter two regulate energy expenditure.
Peripheral control of feeding behaviour

Metabolic state is reected in a diverse array of signals of the brain. Recent investigations have shed light on some of the key hormones and the vagal
set-point) most of the time in most people [39]. The rst step in maintaining this homeostasis is for the brain to inform itself of the metabolic status of
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mechanisms that shape the central response to nutritional challenges (Fig. 1). The vagus nerve The gastrointestinal canal is equipped with a myriad of sensory receptors along its full crown-rump extension [45]. Thus, the taste, texture and mechanic stress of food is reported to the brain to provide an online description of the immediate alimentary state. This information is routed to the nTS primarily via the afferent portion of the vagus nerve, so that vagal activation causes satiation and meal termination. (Parallel neural feedback is also supplied by sensory neurones innervating the oral cavity mediating, e.g. taste, and lesser-studied splanchnic nerves [46].) Vagal afferents are broadly sensitive to gastrointestinal signals, including gastroduodenal distension, the presence of chemically distinct nutrients within the gastrointestinal tract as well as peptides produced by endocrine cells in the gut wall, most prominently cholecystokinin (CCK), a well-characterized satiety signal [47, 48]. Importantly, these signals are integrated within the individual vagal sensory neurone prior to the signal being relayed in the nTS [49, 50]. The neurochemical identity of viscerosensory vagal neurones has remained enigmatic, but these cells likely signal via glutamate [51] and the neuropeptide cocaine- and amphetamine-regulated transcript [52], which inhibits feeding upon brainstem administration [53]. Leptin An appetite-regulating endocrine signal from fat tissue maintaining energy homeostasis had been hypothesized already with parabiosis experiments in the 1950s [34]. The seminal discovery of leptin, the adipocyte-derived protein hormone providing this signal, by Friedman and collaborators in 1994 [54] was a decisive catalyst for much of the current investigation on peripheral modulation of central networks. A little more than a decade later, leptin has been shown to modulate several aspects of energy balance through several different mechanisms and across a wide spectrum of timeframes, alerting the brain to the state of body adiposity [55] and acting as a fat-o-stat. It is now well established that the pronounced obesity in genetically leptin-decient ob/ob mice is due to the loss of a
Fig. 2 Genetically leptin-decient ob/ob mice treated subcutaneously (s.c.) with saline (left) or with leptin (right). The severe obesity in these animals is abolished with leptin replacement therapy. Figure generously provided by Dr Jeffrey M. Friedman.
centrally active feeding-inhibitory messenger, as restitution of the leptin signal in these animals normalizes food intake and body weight [56] (Fig. 2). Serum leptin correlates well to the size of the body fat deposit, and falls with weight loss [57]. This relationship is seen also in obesity, where the combination of hyperleptinaemia and hyperphagia has led to the suggestion that overweight is characterized by leptin resistance [58]. Central actions underlie both leptin-mediated feeding suppression as well as the extensive peripheral metabolic effects of this hormone; thus, e.g. replacement of leptin receptors selectively in the brain of ob/ob mice is sufcient to prevent hepatic steatosis [59]. Insulin Insulin is well recognized as the key glucostatic regulator. Recent data demonstrate that in addition to the control of peripheral glucose uptake, this role also encompasses powerful central effects, in synergism with leptin. First, intracerebroventricular (i.c.v.) administration of insulin decreases food intake [60] via insulin receptors expressed on Arc neurones [61]. The role of insulin in feeding is complicated by the fact that the hypoglycaemia resulting from elevations in serum insulin in itself stimulates food intake. However, when blood glucose changes are compensated for, hypophagia is seen also with increases in peripheral insulin [62, 63], suggesting that the central effects of insulin are anabolic. (This secondary hypoglycaemia may also explain why the insulin secretion triggered already at the sight of a palatable-looking
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meal stimulates appetite (the cephalic phase [64]), an indication that direct sensory input relayed via the cortex can set off powerful appetitive mechanisms.) Secondly, and again similar to leptin, insulin also modulates peripheral energy metabolism via central effects by inhibiting liver gluconeogenesis [65, 66]. Thus, whilst the brain does not depend on insulin for glucose uptake, it is very much interested in what insulin has to say about the metabolic state of the body. Peptide YY (3-36) In addition to CCK, several gut-derived peptides provide alimentary feedback to the central metabolic circuits [67]. Peptide tyrosine-tyrosine (3-36) [PYY(3-36)], a member of the NPY peptide family produced by enteroendocrine cells [68], has recently been shown to act as an important feedback signal from the gut to the hypothalamus. Following a meal, PYY(3-36) is released into the circulation [69], specically stimulated by the presence of lipids and carbohydrates in the lumen of the distal ileum and colon [70, 71]. Peripheral administration of this hormone inhibits food intake and causes weight loss [72, 73]. While some laboratories initially were unable to replicate this effect [74], this may partly be due to discrepancies in technique [75] and the results have since been independently conrmed [76, 77]. The satiety effect of PYY(3-36) is comparatively modest but, importantly, is observed also in humans, including obese patients [73, 78]. Plasma levels of PYY(3-36) rise markedly following ileal resection [79, 80], an observation that has been linked to the weight loss observed in patients undergoing this procedure (S.R. Bloom and C. Le Roux, personal communication). Ghrelin Thus, the gastrointestinal-brain axis has long been viewed as a key channel subserving meal termination with CCK and PYY(3-36) as prime mediator examples. Novel ndings on the hormone ghrelin (produced in stomach and small intestine epithelia [81], see [82]) are challenging this doctrine. Ghrelin is unique as the rst gut hormone shown to stimulate food intake [67]. Both peripheral and central injections of ghrelin result in increased feeding as well as fat mass [8386]. Ghrelin levels
peak sharply in anticipation of a meal in humans as well as experimental animals [87], resulting in stimulation of both feeding and gastric emptying [88] through actions possibly involving the vagus nerve [89], and may thus provide a meal initiation signal. In the hypothalamus, peripherally administered ghrelin mainly activates the NPY neurones [85, 90] and antagonizing the actions of these cells inhibits the orexigenic effect of ghrelin administration [85, 91]. In contrast, the melanocortin pathway does not appear to be primarily involved [90]. Recent reports have proposed that ghrelin is synthesized also in hypothalamic neurones, but this issue remains controversial, in part due to the contradictory claims of the site of central ghrelinergic neurones and the failure to demonstrate ghrelin mRNA in the brain (cf. [92] and [93]). Importantly, a loss of the hunger message relayed by ghrelin has been suggested as the mechanism behind the weight-reducing effects of bariatric surgery [94]. The initial rationale for gastric bypass [95] was that the procedure would produce weight loss by means of malabsorption. However, this turns out to be a transient effect due to the considerable compensatory potential of the digestive system. Nevertheless, weight loss persists, caused instead by a loss of appetite and hypophagia [96]. Concomitant with this effect, a fall in plasma ghrelin is observed following the bypass procedure, in contrast to the ghrelin increase associated with nonsurgical weight reduction, where weight relapse is common [86, 97]. (Note, however, ndings that argue against such a relationship, see [67].) Furthermore, clinical data tie the hyperphagia observed in Prader Willi syndrome to strikingly high plasma ghrelin levels [98]. These results, coupled with the discovery that elevated plasma ghrelin is a marker for future weight gain (D.E. Cummings and J. Krakoff, personal communication) indicate that interfering with ghrelin signalling offers a clinically promising approach to treating eating disorders. Oleoylethanolamide A role for endogenous cannabinoids in appetite regulation has long been suspected from the carbohydrate craving observed in marijuana smoking [99]; indeed, increased appetite is a diagnostic criterion for cannabis intoxication [100]. Neuronal production of cannabinoids is widespread and these
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mediators play an important and general role in the modulation of synaptic transmission [101], with the orexigenic effects likely mediated via central cannabinoid CB1 receptors [102, 103]. However, the lipid family to which the cannabinoids belong also includes other members with opposite and peripheral effects on energy metabolism. Piomelli and colleagues have accumulated evidence that the fatty acid oleoylethanolamide (OEA), chemically but not pharmacologically similar to the cannabinoids, is produced in the duodenum and acts via the vagus nerve to decrease body weight through activation of the nTS [104]. OEA increases the inter-meal latency, an effect distinct from that of, e.g. CCK, which primarily decreases meal size [105]. However, changes in energy expenditure also underlie the OEAmediated weight reduction and are especially pronounced in models of obesity, involving in particular increased fat utilization, whereas glucose homeostasis is relatively unaffected [106]. The catabolic effects are most noticeable as a slowing of body weight gain in growing rats, with OEA synthesis reduced by food deprivation and stimulated in response to increased demands on energy availability such as cold exposure [104]. The metabolic actions of OEA depend selectively and critically on genomic as well as nongenomic actions of the ubiquitous nuclear peroxisome proliferator-activated receptoralpha (PPAR-a) [107]. These results add obesity to the growing list of potential therapeutic applications for nuclear receptor pharmaceuticals. Notably, drugs that target PPAR-a, e.g. gembrozil, are already in clinical use to treat hypercholesterolaemia [108].
Integration of peripheral signals in the Arc

The peripheral signals described above thus act upon the Arc (and nTS, see below) to inuence the central pathways regulating energy balance. In the Arc, receptors for leptin and insulin found on NPY and POMC neurones serve to inhibit transcription of NPY [109, 55] and increase POMC mRNA levels [110 112] via differential second messenger systems [113]. It is becoming evident that insulin, leptin and other metabolically relevant hormones eventually converge not only on a common set of neurones, but indeed also on the same molecules. Recent reports highlight the role of the ATP-dependent potassium current, IK(ATP), as a molecular target mediating rapid, electrophysiological effects, of peripheral
hormones. This K+ conductance is a priori sensitive to the availability of metabolic fuel as a fall in intracellular levels of the energy donor ATP causes the channel to open, leading to K+ inux and hyperpolarization; this mechanism enables neurones expressing IK(ATP) to vary their excitability in response to changes in glucose concentration [114]. Leptin and insulin both hyperpolarize Arc neurones by enhancing IK(ATP) [115, 116], by activating a common enzyme, phosphoinositide 3 (PI3) kinase [116, 117]. It should be emphasized that the transmitter phenotype of Arc neurones expressing IK(ATP) is a controversial issue which remains to be conclusively resolved [118120]. Additional signals likely weigh in on IK(ATP); this current is augmented when the concentration of fatty acid derivatives is increased locally within the Arc by inhibition of lipid oxidation, a message of energy surplus that also decreases food intake [66, 121]. This convergence of nutrient information makes the PI3-kinase/IK(ATP) a key integration node within the metabolic signalling chain, attractive as a therapeutic target. Modulation of the membrane potential of Arc neurones has recently been demonstrated to control glucose homeostasis. Opening of Arc K(ATP) channels via either hyperinsulinaemia or central inhibition of lipid oxidation inhibits vagal efferent (i.e. parasympathetic) gluconeogenic signals to the liver, promoting the use of fat as metabolic fuel [66, 122]. The Arc is also the site of central leptin regulation of glucose homeostasis as selective restoration of Arc leptin receptor expression in otherwise leptin receptor-decient mice is sufcient to correct their hyperglycaemia [123]. These results show that insulin modulates glucose homeostasis by independent peripheral and central mechanisms and emphasize that interconnectivity within brain metabolic regions serve to switch the body between different fuel sources, in parallel to controlling food intake. Interestingly, in obese rats, hypothalamic IK(ATP) channels fail to respond to leptin and insulin [115, 116]. Whether similar defects underlie insulin and/ or leptin resistance in human diabetes and obesity is an interesting possibility, which remains to be investigated. Output from the Arc NPY neurones. Neuropeptide Y is one of the most potent stimulators of feeding known [124], an
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suggests that NPY primarily stimulates appetitive rather than consummatory behaviour [130]. POMC neurones. Pro-opiomelanocortin is a large precursor protein which gives rise to several bioactive peptides. Among these, the melanocortin peptides, in particular a- and c-melanocyte-stimulating hormone, have been shown to exert potent anorexigenic effects when administered i.c.v. [131, 132]. Central melanocortin effects are mediated by the melanocortin 3 and 4 receptors (MC3R and MC4R, respectively; Fig. 3b). Deletion of the genes for either POMC, MC3R or MC4R result in obesity in mice, suggesting that the melanocortin system is crucial in maintaining body weight [133135] as supported by similar ndings in humans (see below). MC4R)/) mice also increase their feeding in response to a high fat diet, in contrast to wild-type littermates where a reduction is seen and ob/ob mice, which maintain the same intake as with regular chow [136], underlining the importance of the melanocortin system for adjusting food intake in response to caloric variations. In addition, the hallmark hypophagia seen in disease models as diverse as renal failure, immunological challenge with lipopolysaccharide (LPS) and tumour implants is ablated. The obesity in MC4R-decient animals is partly due to changes in energy expenditure, such as decient diet-induced thermogenesis [136]. The anatomical substrate for this effect may be a direct projection from the POMC neurones in the Arc to the preganglionic sympathetic neurones in the spinal cord [137139] constituting a link between the metabolic integrator and the autonomic effector system. Interestingly, the spinal projection sets the POMC neurones apart from the neighbouring NPY neurones which otherwise exhibit very parallel innervation patterns. However, it should be pointed out, that in humans, the melanocortin system appears to be more geared towards regulating feeding behaviour, with a proportionately smaller role in peripheral metabolism [140]. NPYPOMC interactions. Interactions between the Arc populations allow the NPY neurones to control the activity of the POMC cells via two mechanisms. First, NPY neurones coexpress agouti gene-related peptide (AGRP), an endogenous melanocortin antagonist [141143]. Thus, at the axon terminal, melanocortin action can be blocked by simultaneous
Fig. 3 Expression of NPY and melanocortin receptors in the mouse brain. In situ hybridization histochemistry (a) shows the distribution of NPY Y1 receptor mRNA detected as silver grains in a coronal section, revealing dense expression in the cerebral cortex and nuclei in the amygdala, thalamus and hypothalamus. In panel b, green uorescent protein (GFP) is expressed in a neurone under control of the melanocortin (MC) 4 receptor promoter; note strong immunoreactivity throughout cell soma and dendrites. A Nissl-stained coronal section (c) shows neurones clustered to form the paraventricular hypothalamic nucleus (PVH) alongside the third ventricle. The PVH constitutes a central integrative hub within the metabolic circuitry. (d) Immunohistochemical for GFP (indicating the presence of the MC4 receptor) and in situ hybridization for NPY Y1 receptor mRNA have been combined in a section from the amygdala, revealing the coexistence of these receptors in neurones downstream of the Arc. Figure produced by Drs Toshiro Kishi and Joel K. Elmquist. Reprinted with permission from Macmillan Publishers Ltd.; Molecular Psychiatry 2005;10:132146.
effect that has been conrmed by various approaches [40]. While there is conicting data on whether deletion of the NPY gene produces hypophagia (cf. [125] and [126]), the obesity of ob/ob mice is attenuated when combined with an NPY)/) genotype [127], suggesting that NPY is an important mediator of central leptin signalling. Stimulation of feeding appears to be transduced predominantly via postsynaptic NPY Y1 receptors, as determined from pharmacological and genetic engineering studies (reviewed in [128], Fig. 3a). However, the synergistic actions of multiple NPY receptor subtypes participate to produce orexigenic effects in vivo [129]. Detailed behavioural analysis of those effects
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release of AGRP, and in agreement with such an arrangement, a single i.c.v. administration of AGRP causes an impressively long-lasting (one week) suppression of food intake [144]. Secondly, at the cell body level, POMC neurones are innervated by NPY-ergic terminals [145] and express the Y1 receptor [146], through which NPY causes a powerful membrane potential hyperpolarization (i.e. inhibition) [147]. Surprisingly, no reciprocal innervation has yet been described and Roseberry et al. [147] did not detect any changes in the electrical properties of NPY neurones using a melanocortin analogue. Thus, there may exist an asymmetrical interaction in the Arc favouring the orexigenic NPY/AGRP message over anorexigenic melanocortin signalling. However, an inhibitory inuence over the NPY neurones may be provided by PYY (3-36), which is a selective agonist of the inhibitory Y2 autoreceptors [148] expressed by these cells [146]. Such gastrointestinal negative feedback has been proposed as the mechanism whereby PYY(3-36) inhibits feeding as no such effect is observed in mice genetically decient for the Y2 receptor and application of the peptide inhibits the electrical activity of Arc NPY terminals [73]. This effect is relatively selective as disruption of other relevant metabolic pathways does not affect the satiety effect; the PYY(3-36) effect persists both after vagotomy and in MC4)/) mice [76], suggesting that neither the nTS nor the Arc POMC neurones are directly involved. Classical transmitters: glutamate and GABA. While much of the current research on the central regulation of energy balance focuses on the role of peptides, it should be emphasized that in the hypothalamus, as in the rest of the brain, the key chemical mode of communication between neurones is via amino acid transmitters, i.e. excitatory glutamate and inhibitory c-amino butyric acid (GABA). Indeed, in the absence of glutamate and GABA-mediated transmission, little remains of hypothalamic synaptic activity [149, 150]. The major function of peptides, in addition to their genomic effects, is likely to modulate the synaptic transmission of classical transmitters [151] with which they coexist [152]. Interestingly, glutamate N-methyl-d-aspartate (NMDA) receptors have been found to stimulate feeding with remarkable anatomical specicity within the lateral hypothalamic area (LHA), in comparison with other hypothalamic regions tested and the amygdala
[153]. Infusion of NMDA antagonists locally within the LHA blocks both agonist-induced and deprivation-induced food intake, indicating the involvement of endogenous glutamatergic tone in natural feeding [154]. Histochemical studies suggest that within the Arc, NPY neurones largely contain GABA, whereas POMC neurones signal via glutamate [155, 156]. Downstream targets of the Arc. The downstream cellular effects of NPY are still mysterious. It was initially assumed that feeding-promoting neurones in loci sensitive to NPY orexigenesis were excited by NPY. However, all known members of the NPY receptor family couple to inhibitory second messenger systems [128]. Electrical excitation has been proposed to come about in the form of disinhibition via NPY-mediated suppression of GABA-dependent inhibitory postsynaptic currents [157, 158], with melanocortin stimulation producing the opposite result, i.e. inhibition via stimulation of GABA release [157]. However, that does not explain the role of postsynaptic Y1 receptors, which exist throughout the hypothalamus [146, 159, 160] (Fig. 3a). The most potent orexigenic effects of NPY are seen within the perifornical region/LHA [124], where NPY/AGRP-ergic terminals appear to target two separate populations of neurones expressing the neuropeptides hypocretin (Hcrt; also known as orexin) and melanin-concentrating hormone (MCH; Fig. 4, [142, 161, 162]). This pathway is of interest as Hcrt and MCH potently modulate wakefulness [163167], providing a means for metabolic signals to control arousal state. Surprisingly, in a recent investigation of the electrophysiology of the LHA neurones, melanocortin stimulation did not affect the electrical properties of MCH-expressing cells, whereas both these and Hcrt-expressing cells were inhibited by NPY [168, 169]. Furthermore, microinjection of NPY into the LHA appears to activate a group of neurones distinct from those expressing Hcrt or MCH [170]. As with all neural interactions, it is important to bear in mind that the activity of neurones can be inuenced via several independent mechanisms, including (but not exclusively) electrical and transcriptional effects, and that different changes proceed along different temporal scales. Thus, a functional Arc-LHA pathway cannot be excluded. Nevertheless, these data invite a re-evaluation of the role of Hcrt and MCH as downstream mediators of the NPY and POMC neurones.
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Fig. 4 Integration in higher brain regions determines the central response to changes in peripheral metabolic state. Schematic illustration of connections between brain regions responsible for coordinating the behavioural somatomotor (i.e. food intake), autonomic and endocrine (the latter two regulating energy expenditure) responses that together constitute the motivated ingestive behaviour used by the nervous system to meet nutritional challenges. The antagonistic orexigenic NPY and anorexigenic POMC neurones in the Arc project in parallel paths to numerous subcortical nuclei [including the bed nucleus of the stria terminals (BST), the medial preoptic area (MPO), the paraventricular nucleus of the thalamus (PVT), several hypothalamic nuclei, e.g. the dorsomedial nucleus (DMH), the amygdala (Amgdl), the serotonin-containing system in the raphe nuclei, the periacqueductal grey area (PAG) and the parabrachial nucleus (PBN)] distributed throughout the brain. A projection to neurones expressing melanin-concentrating hormone (MCH) or hypocretin (Hcrt) in the lateral hypothalamic area (LHA) provides an indirect pathway to the cerebral cortex for metabolic signals relayed via the Arc. The cortex in turn projects back heavily to both the LHA and other feeding-regulatory regions. In addition, the LHA also receives an inhibitory input from the shell of the nucleus accumbens (AcbSh), which in turn is modulated via prominent excitatory inputs from the prefrontal cortex (PFCx). Thus, the LHA is positioned to integrate both homeostatic and reward-related signals in the gating of food intake. Energy expenditure is modulated via outputs from the Arc to neuroendocrine neurones in the paraventricular hypothalamic nucleus (PVH), which control release of, e.g. thyrotropin-releasing hormone and adrenocorticotropic hormone from the pituitary gland. Energy expenditure is also regulated by projections from POMC neurones in the Arc and descending pathways from the PVH to autonomic preganglionic neurones in, e.g. the dorsal motor nucleus of the vagus (DMX; parasympathetic) and spinal cord intermediolateral cell column (IML; sympathetic). Note that ascending projections from the brainstem, which provide parallel important metabolic inputs to the brain, have not been included in the gure. See text for details.
Circadian regulation of metabolic processes. In addition to the various controls summarized above, metabolic processes also follow strict circadian variations as recently underscored by the demonstration that inactivation of key genes maintaining circadian rhythmicity results in manifest metabolic syndrome in mice [171]. Thus, for example, in rats the active period of the day is immediately preceded by coordinated peaks in hepatic glucose output (via the sympathetic nervous system) and glucose uptake in
striated muscle (a parasympathetic effect; see [172]). Buijs et al. [173] have investigated which brain regions are responsible for this synchronization. Using anatomical tracing they nd that the chains of neurones innervating liver and muscle are separated all the way through brainstem and hypothalamus to distinct populations of preautonomic master neurones in the suprachiasmatic nucleus [173], the brain region maintaining circadian rhythmicity and entrained by direct retinal input [174, 175]. The
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distinct pathways originating in the suprachiasmatic nucleus are particularly interesting in conjunction with the discovery that the autonomic inputs to intra-abdominal and subcutaneous fat stores are also separate [176]. In humans, shift work [177] and sleep deprivation [178] are associated with increased adiposity, ndings that have been linked to the sleep-associated peak in leptin secretion [179]. However, this anatomically separate innervation indicates that loss of periodicity in the circadian input to adipose tissue may disrupt the balance between different fat compartments leading, in turn, to manifestations of the metabolic syndrome, which is correlated to abdominal but not subcutaneous fat accumulation [180].
Contributions of hind- and forebrain to feeding regulation

As mentioned above, the brainstem provides a port for vagal and other neural sensory signals into the brain. Classical accounts of brain regulation of feeding described two systems balancing each other: the hypothalamus, monitoring the periphery for signals alerting central circuits to diminishing energy stores, and the brainstem, receiving oral and gastrointestinal information as an online signal of the amounts and qualities of the food that was being ingested. This arrangement would allow the hypothalamus to function as a long-term control orchestrating meal initiation and the brainstem served as a short-term control for meal termination. Much of our knowledge on the different contributions of the fore- and hindbrain in meal regulation comes from a lesion model developed by Grill and Norgren [33]. Disconnecting the forebrain (which includes the hypothalamus) produces a rat incapable of the motor activation necessary for normal feeding. However, if this animal whose brainstem remains intact is provided sucrose solution via an intraoral cannula, intake can be measured as the solution consumed until the meal is terminated as the animal lets solution drip out of the mouth. These decerebrated rats maintain the ability to terminate their meal in response to changes in gastrointestinal feedback, but are unable to compensate for variations in the caloric value of the fed solution, resulting in anorexia if the sucrose concentration is reduced. Similarly, removal of the post-oral feedback (by e.g. vagus nerve transection or gastric
drainage) leads to increases in meal size as well as duration [181, 182], although there is a compensatory delay in the latency to meal initiation, possibly mediated by the hypothalamus. These results underscore the role of the Arc as a metabolic sensor. It should be pointed out that an intact Arc is not necessary for meal initiation humans and animals with selective lesion of this region not only eat, they eat copiously [29, 183185]. It is now becoming evident that the brainstem can integrate much the same signals as have been shown to modulate hypothalamic activity. Leptin receptors are expressed at several strategically located brainstem sites, and selective stimulation of these receptors suppresses food intake at doses comparable with those used in forebrain injections [186, 187]. Here, leptin activates the same medial region of the nTS that is stimulated by gastric distension [188], suggesting an anatomical site of integration of long- and short-term feeding controls. Likewise, melanocortin agonists can reduce feeding and body weight by brainstem mechanisms [189]. Interestingly, the neurones in the nTS mediating the viscerosensory signal may also be POMC-encoded [43, 190], a nding that puts our understanding of melanocortin-mediated meal suppression in a new light. Orexigenic effects of ghrelin are also seen with selective local administration both in the hypothalamus [84] and in the brainstem [191] (Fig. 5a,b). Finally, glucosensitive neurones have been recorded in the nTS [192]. Thus, the nTS is in no way a
Fig. 5 Ghrelin increases food intake following brainstem administration. Unilateral injection of 10 pmol (but not 5) of ghrelin (black bars) into the dorsal vagal complex, including the nucleus tractus solitarii, results in a signicant increase of food intake both 1.5 and 3 h after drug administration compared with vehicle (white bars), in an experiment by Faulconbridge et al. [191]. Reprinted with permission from the American Diabetes Association; Diabetes 2003;52:22602265.
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passive transducer of viscerosensory signals, but serves to integrate numerous indices of the animals metabolic state. This conclusion is supported by the observation that the hyperphagia of rats that lack leptin receptors is caused by larger meal size (i.e. meal termination delay) rather than an increased number of feeding bouts [193], suggesting an action localized in the hindbrain. However, the response to CCK (i.e. brainstem satiety signalling) as well as normal meal size is restored in these animals following selective re-establishment of leptin receptor expression in the Arc. Weighed together, these data emphasize that actions of metabolically relevant hormone take place at a few, but distributed, sites in the brain contributing to a coordinated feeding response.
system. Another alternative is that the reciprocity may produce a reverberating signal, such as the large-scale oscillations described in, e.g. thalamocortical systems [204]. Possibly, such persistent activity may be important in the triggering and maintenance of an anabolic response. The hierarchical organization of the metabolic circuits and its relationship to behaviour presents a major future scientic challenge. (For further discussion of the systems organization of energy balance regulation, the reader is referred to recent exhaustive reviews [37, 38].) Coordinating the metabolic output It also remains to explain how the divergence convergence organization of the Arc/nTS projections interdigitates with the efferent networks underlying the nal metabolic response. As already mentioned, motivated behaviours (classically divided into ingestive, reproductive and defensive) involve three distinct outlets: components of the autonomic and neuroendocrine systems as well as coordinating the overall behaviour of the animal [44]. Activity within these three effector systems is hypothesized to be organized by a collection of cell groups within the medial hypothalamus area, collectively termed the hypothalamic visceromotor pattern generator network [205], which subsequently recruits elements within a behavioural control column, spanning the mes- and diencephalic midline [206]. Separate groups of control column nuclei produce ingestive, reproductive and defensive behaviours, but connections between these networks allow them to interact for purposes of mutual exclusion so that only one behaviour is expressed at once [207]. The paraventricular nucleus (PVH; Fig. 3c) is a crucial control column module for ingestive behaviour. The PVH collects metabolic information from oropharyngeo- and viscerosensory receptors and humoral signals (both directly and via the Arc), and is regulated by biological rhythms via the suprachiasmatic nucleus and by the overall state of the animal as reported from the cerebral hemispheres via relays in the septum [206]. Output from the PVH, in turn, employs all three outlets described above: endocrine via neuroendocrine neurones controlling pituitary hormone release, autonomic via direct projections to
Beyond the primary sensors: CNS integration of hunger and satiety signals
As in all matters involving the brain, behaviour begs the question: What are the pathways? For the metabolic signals to produce behaviour they need to proceed further into the brain beyond the primary sensors in the Arc and nTS and ultimately engage regions that initiate and organize behavioural, autonomic and endocrine response patterns. Histochemical studies have revealed that (i) the Arc projections diverge widely throughout the brain [194197] including, via indirect pathways, a massive cortical innervation [198] (Fig. 4), (ii) the NPY and POMC populations project in remarkably parallel paths [196] and may converge on the same cells as supported by the widespread coexistence of Y1 and MC4 receptors [199] (Fig. 3d), and (iii) the nTS innervates largely the same nuclei as the ascending projections from the Arc [196, 200 202]. This circuitry indicates that integration between the primary metabolic sensors in the Arc and nTS is a distributed phenomenon, and it has been suggested that this arrangement allows for motivational state to be weighed into the network before reconvergence and the nal decision for a proper metabolic response is made [40]. In addition to this scheme, extensive reciprocal projections connect the Arc with its target regions [203]. The functional implications of this arrangement are not clear at present. There may exist a sequential arrangement hidden within the network that has so far eluded the techniques used to investigate the
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preganglionic neurones in the spinal cord intermediolateral cell column (sympathetic) and the dorsal motor nucleus of the vagus (parasympathetic), and behavioural (i.e. somatomotor) via several pathways innervating the brainstem [137, 208 210] (Figs 1 and 4). The hierarchical arrangement upstream of these motor nuclei bears some similarity to the basal ganglia organization for the control of conscious movement [206]. The details of the underlying anatomy remain mysterious, but it is clear that, rather than a simple sequential organization where information ows neatly from one collection of neurones to another, we are faced with an interconnected series of hubs that collect, integrate and disseminate information.
is sufcient to redirect behaviour. Intriguingly, the predicted transmembrane domains of NPR-1 display considerable homology to mammalian NPY receptors [212], suggesting that similar molecular components underlie related behaviours throughout evolution. Recent data demonstrate that within this network an important upstream regulator of NPR-1mediated feeding is oxygen concentration, showing how external cues reset behaviour [215, 216]. Aplysia In Aplysia, a meticulously dissected network has been highly informative in characterizing the neural mechanisms underlying various behavioural components. Aplysia feeding can be initiated by sensory stimulation of the lip and is consolidated by arousal caused by the exposure to food. In parallel with the feeding central pattern generator (CPG) circuit, a network controlling arousal is triggered, which then feeds back into the CPG [217]. Termination of food intake is achieved by switching ingestion to the opposite behaviour of egestion [218]. Separate motor neurones within the CPG effectuate ingestion and egestion. Switching the balance between these neurones is elegantly accomplished by recruiting a single additional interneurone into the circuitry via an electrical synapse [219]. Feeding patterns in this social mollusc also differ substantially in the absence or presence of other animals; company is an important incentive for feeding. Pheromones secreted from other Aplysia stimulate a neurone directly driving the appetitive phase of feeding, which also excites a control neurone for the consummatory phase so that these behaviours are properly organized, leading to larger and more frequent eating bouts [220]. These studies provide information on how organization within a neural system translates into behaviour, with potentially broad implications considering the surprisingly large overlaps between human and mollusc feeding behaviour. Importantly, they may shed light on the process of selection within the behavioural repertoire and why we eat in apparent violation of homeostatic mechanisms when our fat stores are lled to the brim.
Food intake in lower organisms: models for the organization of behaviour

Intriguingly, an improved understanding of the organization of feeding behaviour is now coming from studies of lower organisms. Animals such as the nematode Caenorhabditis elegans and the sea slug Aplysia present several technical advantages: behaviour is easily divided into discrete sequences, the nervous system consists of a limited number of neurones whose electrical properties and interconnectivity has been characterized in detail, and, in the case of C. elegans, the genome is highly accessible for molecular manipulation. This knowledge makes it possible to understand how nature organizes physical networks to efciently initiate, organize and terminate behaviour. Caenorhabditis elegans Feeding in C. elegans is polymorphic; depending on genetic background animals will feed either alone or in aggregates [211213]. Naturally occurring variations in a single amino acid position of the neuropeptide receptor NPR-1 (for neuropeptide receptor resemblance-1) translate into either a solitary or a social feeding phenotype [212]. Activation of NPR-1, by shifting network properties, leads to activation of social feeding behaviour, and the amino acid substitution in NPR-1 determines the response to stimulation with the neuropeptide ligands p 18 or )21 [214]. Conversely, null mutations in the npr-1 locus alter the balance in favour of solitary feeding [214]. Thus, a single gene
Food reward: role of the nucleus accumbens

However, to elucidate the neural organization of feeding in complex vertebrates, it is necessary to
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consider that our choice of food is not simply a function of energy supply and demand, but also very much linked to reward value. Homeostatic systems active within the brain operate at the mercy of motivational states. The motivational state is a product of, inter alia, limbic inuences relayed in part via the amygdala, and reward factors. Obviously, adding reward experience to food is a means of, e.g. avoiding consumption of foods whose taste indicate the presence of invasive microorganisms, but also promoting those whose taste signals particular nutritional value. As a result, pairing feeding with pleasure may override normal satiety mechanisms, resulting in hyperphagia and obesity. The concept of reward is intimately linked to that of addiction, and it has been suggested that obesity is a consequence of an addiction to food [221]. Drugs of abuse converge upon the mesolimbocortical system to produce reward, specically by enhancing dopamine release in the nucleus accumbens (Acb) of the forebrain as a nal common pathway [222]. There is little doubt that changes in dopaminergic transmission affects food intake. Indeed, animals unable to produce brain dopamine die of starvation unless fed by gavage [223], and a common side-effect of neuroleptics affecting dopamine signalling is obesity [224]. However, novel data suggest that dopamine primarily acts to reinforce behaviours at the initial encounter with a novel reward, but the release of dopamine decreases once the behaviour has been established within the behavioural repertoire [225]. Thus, whilst dopamine modulates learning and locomotion associated with motivational behaviour, it appears not to modulate feeding behaviour per se; blocking Acb dopamine signalling does not alter total food consumption in starved rats, although it suppresses ambulation associated with feeding [226]. However, transmitter systems other than the dopaminergic system connect Acb to components of the metabolic circuitry [227]. Notably, chronic access to a preferred avour (chocolate-fat solution) produces the same transmitter changes in the Acb as chronic morphine or ethanol, suggesting a common reward mechanism for palatable food and conventional drugs of abuse [228]. These changes include increased transcription of opioid peptides such as enkephalin. In turn, stimulating lopioid receptors in the Acb increases intake of fatenriched foods with high palatability value [229],
which may be interpreted as positive reinforcement. This effect is not seen following inhibition of neural transmission in the basolateral amygdala (BLA) or the LHA [230]. The connection between the BLA and forebrain cortical regions has been implicated in gauging food palatability, and an intact BLA is required for determining the reward value embedded in sensory input [231]. In contrast, the central amygdala (CeA) serves more like a general gatekeeper of feeding as inactivation of this subnucleus blocks consumption of all foods [230]. This dichotomy may be explained by the different projections of the BLA (innervating higher forebrain regions such as the prefrontal cortex) and the CeA (aimed towards the postulated hypothalamic and brainstem feeding pattern generators). The connection between the Acb and the LHA has also been shown to modulate food intake (Fig. 4). Kelley and colleagues have shown that blocking excitation of the GABA-encoded Acb results in hyperphagia, an effect contingent upon intact transmission in the LHA [232]. Glutamatergic excitation in the Acb is predominantly supplied by the cortex, so that this cortex-Acb-LHA pathway could offer the prefrontal cortex in particular a channel for inhibiting feeding behaviour in favour of other behaviours [227]. These data indicate that in the regulation of ingestive behaviour, the Acb is indeed at the interface between motivation and action as originally postulated for this structure [233].
Studies on the food intake experience in humans and monkeys: relevance for understanding obesity
Dening the cortical involvement in feeding behaviour is likely vital for understanding human eating disorders. Crosstalk between the cerebral cortex and primary sensors is extensive; impressively, the hypothalamus provides the largest external cortical input with the exception of the thalamus [198], and reciprocal connections are plenteous [234]. Investigations of monkeys and humans by Rolls and collaborators have revealed that the sensory properties of food are processed in two steps in the cortex [see 235]. The insular cortex, functionally and neuroanatomically implicated as viscerosensory cortex [236], acts as a primary taste cortex where these individual features, i.e. taste, appearance, smell and texture, are
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represented to determine which food is being ingested. Individual neurones are sensitive to single stimuli, and do not adapt their ring even when the stimulus (e.g. glucose) has been present for a long time [237]. The orbitofrontal cortex (which receives direct input from the insular cortex), however, acts as a higher-order taste cortex, which determines how pleasant a particular food is. Orbitofrontal neurones are broadly tuned to react to multiple sensory features, so that the ring of these cells result from the combined inputs from several sensory modalities [238], although different cells respond to different quantitative combinations of stimuli. The subjective pleasantness rating is proportional to orbitofrontal activation and this activation drops accordingly when a particular food is eaten to satiety [239] (Fig. 6). Thus, computations within the orbitofrontal cortex confer hedonic qualities upon the feeding circuitry, a role whose importance in human appetite may be underestimated when extrapolating from rodent studies. The orbitofrontal cortex feeds directly into the LHA, which may thus constitute an important nexus for linking the subjective experience of food with homeostatic signals. The relationship of the hedonic/pleasure experience to human obesity has begun to be addressed in
neuroimaging studies, further emphasizing the cortical parcellation of different feeding-related processing. Whereas during hunger, activation is observed predominantly in regions associated with the regulation of emotions (limbic and paralimbic cortex), satiety is followed by activation in the prefrontal cortex, postulated to play a role in the inhibition of inappropriate behaviours [240]. The presentation of a palatable sweet solution after a day and a half of fast resulted in increased signal from the insular cortex [241]. Moreover, almost all observed changes are accentuated in obese compared with lean subjects, i.e. both increases and decreases in activity are of greater amplitude [241] (Fig. 7). These differences are not exclusively accounted for by the hyperglycaemia and hyperinsulinaemia manifest in obese subjects. The functional implication of the intensied patterns of activation and inactivation in obese subjects is not clear at present, but may be of pathophysiological importance. Indeed, these responses persist also after weight loss in postobese subjects [242] suggesting that they are not a consequence of the overweight as such, although it is not known if such accentuated responses are seen also prior to the development of obesity. Elucidating these mechanisms may be signicant also for understanding the human response to food advertisements.
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banana odour
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mango odour
Blackcurrant odour
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Fig. 6 Neurones in the orbitofrontal cortex decrease their ring in response to a particular food as that food is consumed to satiety. Extracellular recording from an odourresponsive neurone in the orbitofrontal cortex of a male macaque. The ring rate of one neurone in response to different odours was recorded whilst the animal consumed a blackcurrant juice. As satiety increases (lower panel), the electrophysiological response to blackcurrant odour diminishes, whereas the response to unrelated odours [banana, mango, phenyl ethanal (pe), citral (ct), onion (on)] is unaffected or elevated. Figure produced by H.D. Critchley and E.T. Rolls and is used with permission from the American Physiological Society; J Neurophysiol 1996;75:16731686.
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Fig. 7 Lean and obese subjects show differences in brain activation during different states of hunger. Statistical parametric maps of signicant brain responses (P 0.005, not corrected for multiple comparisons) to hunger and early satiety in obese (top row) and lean (bottom row) subjects, respectively, at 4 mm above (left images), 4 mm below (middle images), and 16 mm below (right images) a horizontal plane passing through the anterior and posterior commissures (coordinates from the Montreal Neurological Institute). The right hemisphere in each section is on the readers right. The T-value colour-coded areas were regions of the brain in which signicant changes in blood ow (a marker of neural activity) were detected in response to hunger (from yellow to white, in increasing order of T-value), as stimulated by a 36-h fast, or in response to early satiety (from blue to green, in increasing order of T-value), as stimulated by consumption of a satiating liquid meal [304]. The gure is intended for visual inspection only of several brain regions, where signicantly greater responses in obese compared with lean individuals were detected, including the middle temporal gyrus (TEMP) insula (INS), dorsolateral prefrontal cortex (DLPFC), hippocampus (HIPP), temporal pole (T.POLE), orbitofrontal cortex (OFC), and ventrolateral prefrontal cortex (VLPFC). Figure generously provided by Dr Angelo DelParigi.
Development of the feeding circuitry

A series of recent studies have shed light both on the normal ontogenetic development of hypothalamic circuits as well as how these processes are inuenced by the nutritional state of the young animal, with important implications for the aetiology of obesity. At birth, the hypothalamus is rather sparsely innervated by Arc NPYergic bres, and in, e.g. the PVH a substantial NPY/AGRP innervation is seen rst at postnatal day (P) 15 [197, 243, 244]. Similarly, whilst Arc NPY and AGRP mRNAs are detectable from birth, levels peak at P15, and drop to adult levels by P30 [244] (Fig. 8). This development parallels the maturation of the ability to regulate suckling in response to caloric demands [245], linking changes within the Arc metabolic sensor
and adult control of feeding. Notably, failure in the development of the Arc is associated with fatal anorexia in a genetic model [246, 247]. It should be mentioned, that during the early postnatal period, and under certain physiological circumstances, transient expression of NPY in other hypothalamic nuclei can be seen [243, 248]. The role of these transitory NPY projections remains to be determined. As the Arc provides a main conduit for leptin, it is perhaps not surprising, given these data, that pups are unable to respond to leptin by changing their food intake [249], nor to ghrelin [250]. Yet, there is a pronounced peak in serum leptin prior to weaning [251]. Recent data from Bouret et al. [252] suggest that a postnatal leptin surge is essential for the development of Arc projections. In adult ob/ob mice, there is a distinct paucity of Arc-derived terminals.
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Fig. 8 Arc NPY/AGRP projections to the PVH develop during the postnatal period in the rat. Figure displays confocal micrographs of double-label immunouorescence for NPY (red) and AGRP (green) in the PVH. Double-labelled bres are shown in yellow. These images demonstrate that at postnatal day 5 (P5) that there are minimal Arc NPY/AGRP projections to the PVH, whilst there is an abundance of NPY bres that originate from other sources. By P10 there is a signicant concentration of Arc NPY/AGRP projection in the PVH, but they do not reach the adult levels until around P15. Images represent a 10-lm thick collection of optical sections collected at 0.5-lm intervals. Images were captured with a 25 oil objective (0.75 NA) and represent an area of 400 400 lm. Figure generously provided by Dr Kevin Grove.
However, administration of leptin to ob/ob mice during early development, but not in adulthood, results in innervation patterns similar to what is seen in lean littermates, in parallel with a normalization of body weight. These data provide a novel mechanism for how nutritional signals in the early postnatal stage exerts long-lasting effects on the metabolic wiring in the adult. It will be of interest to determine if similar mechanisms are at play in the development of the brainstem-vagal system. In this context, the importance of the prenatal metabolic environment should also be remembered. Gestational diabetes and obesity is associated with obesity
in the offspring of both rats [253] and humans [254]. An extensive long-term study is currently in progress to investigate what changes can be seen in central metabolic circuits in nonhuman primates following intrauterine exposure to diabetes [255]. Conversely, changes in hypothalamic circuitry during senescence may contribute to the loss of appetite that often accompanies ageing [17]. Such changes are observed in older rats, who display signicantly lower levels of expression of NPY [256] and POMC, as well as POMC-positive neurones [257] and diminished dendritic arbours [258] in the arcuate nucleus compared with younger animals.
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Mechanisms of anorexia in infection and cancer

The central systems mediate not only obesity but also anorexia of various aetiologies. Infection-based anorexia is a well-established and clinically highly relevant model [259], which has been instrumental in uncovering the pathways through which microorganisms cause reduced food intake. Bacterial components such as LPS from Gram-negative bacteria and muramyl dipeptide from Gram-positive bacteria activate CD14- and Toll-like receptors on host T-cells to induce production of cytokines such as interferon-c; these results are corroborated by experiments employing genetic removal of strategic components along the pathway [260]. Cytokines are produced peripherally, but activate vagal afferents [261]. In addition, cytokines stimulate prostaglandin production via the enzyme cyclooxygenase 2 (COX-2) in cerebral endothelial and perivascular cells [262]. This latter pathway is important for the induction of LPSinduced anorexia, and can be blocked with indomethacin and other, more selective, COX-2 inhibitors [263]. Further downstream, the prostaglandins activate neurones producing serotonin (5-HT; [264]), a known anorexigenic transmitter [265, 266], which in turn has recently been shown, via 5-HT2C receptors, to stimulate melanocortin signalling [267]. Thus, the signalling cascade set off by pathogenic bacteria ultimately results in activation of the central anorexigenic system. These results may shed light also on the anorexia accompanying noninfectious inammatory conditions. In this context it is interesting to note that, based on structure and signalling pathways, leptin itself belongs to the cytokine family [268, 269]. While anorexia is an important component also of wasting in cancer patients, nutritional supplements only alleviate part of the cachectic syndrome [270], which accounts for a fth of cancer deaths [271]. Cachexia differs from starvation in that both adipose and lean mass is lost, whereas starvation primarily decreases fat stores [272]. A main explanation for this relationship is that many cancer tumours secrete proteins, e.g. proteolysis-inducing factor [273], which suppress protein synthesis in skeletal muscle, via activation of an ubiquitin proteolytic pathway [274]. Parenteral nutrition may thus be of very limited value to the patient if such catabolic mechanisms are not interrupted. However, it turns
out that a polyunsaturated fatty acid found in sh, eicosapentaenoic acid (EPA), suppresses the activity of the proteolytic complex whilst simultaneously inhibiting tumour growth [275]. This nding has promising bedside implications; adding EPA to the diet of cancer patients attenuates muscle degradation and stabilizes body weight [276].
From rodent to human: genetic dissection

In few elds of medicine is the question of nature versus nurture more immediate than in the regulation of body weight. While it is evident that the incidence of obesity has accelerated far more rapidly than can be explained by population shifts within the genome, it is also true that individual differences determine how we react in an energy-dense environment. Aptly summed up by Olden and Wilson [277]: genes load the gun, environment pulls the trigger. Studies of monozygotic twins show that the heritable component of obesity equals that of height and surpasses virtually every other major disease studied, e.g. breast cancer, schizophrenia, cardiovascular disease [278280]; some 40% of obesity can be attributed to genetic causes [281]. In a series of elegant studies, in particular by ORahilly, Farooqi and their colleagues, it has been shown that mutations in several components of the anorexigenic signal chain, including leptin [282] (Fig. 9), the leptin receptor [283], POMC [284] and neuropeptide processing enzymes [285] result in severe early-onset obesity in humans. While these monogenic disorders incontrovertibly demonstrate that genetic abnormalities can cause obesity, it cannot automatically be concluded that mutations and sequence variants are common causes of the metabolic syndrome. However, it is now becoming apparent that mutation of a particular key signalling protein, the MC4R [286], accounts for as many as 5% of cases of severe obesity [140, 287289]. There is a remarkably solid relationship between the severity of the mutation, as revealed in in vitro assays, and the size of a test meal consumed by the patient [140]. Indeed, the heritable component is almost exclusively represented by increased intake of energy, with only a small component accounted for by changes in resting metabolic rate [140]. (In contrast, in the mouse MC4R)/) counterpart, decient energy expenditure is an important factor underlying overweight [136].) The sometimes
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Fig. 9 Leptin deciency in humans responds to leptin treatment. A 3-year-old boy with congenital leptin deciency with severe obesity (body weight 38 kg; BMI SD 7.2) (left). On the right, the same patient, after four years of daily subcutaneous administration of recombinant leptin. Leptin treatment results in a dramatic decrease in adiposity (body weight 29 kg; BMI SD 0.9) and normalization of all metabolic abnormalities including hyperinsulinaemia. Figure generously provided by Drs Sadaf Farooqi and Stephen ORahilly.
modest phenotypes observed in rodent gene knockout experiments (e.g. NPY gene deletion [125]) have been interpreted as evidence for a high degree of redundancy within the system underlying metabolic regulation. However, genetic studies such as these (as well as, notably, observed in nematodes [212]), suggest that there are weak points distributed throughout the system where minute changes in nucleotide sequence can have profound effects on the expression of behaviour. These vulnerable links along the metabolic signalling chain offer promising targets for therapeutic intervention.
Therapeutic prospects
As pointed out in the Introduction, effective treatments for eating disorders are short in supply and urgently needed. While much can be gained simply by increased efforts to educate patients in the benets of weight loss and exercise [290, 291], it is also clear that such therapies in many cases fail in the absence of adequate pharmacological buttress. The anti-obesity drugs presently used in clinical practice have relatively modest effects, and others still have been withdrawn due to intolerable cardiovascular adverse effects [22]. These drugs have often
targeted broadly distributed systems, e.g. serotonin pharmacology, and it is perhaps not surprising that alterations ensue within multiple body functions. Another issue to consider is the timing of administration of feeding-regulatory drugs, which may be more crucial than in any other therapeutic application (T. Bartfai, personal communication). However, based largely on the research summarized above, several novel compounds are now being tested in clinical trials, phases II and III [22, 292]. Many of these compounds target neuropeptide systems. The selective neuroanatomical distribution of many neuropeptides may provide an advantage in attempting to minimize side-effects, and whilst the eld of peptide-based pharmaceuticals has not lived up to initial hopes, the clinical experience from opioid drugs such as morphine and naloxone [293] suggest that interfering with peptide signalling can produce powerful neuropsychiatric effects in humans [294]. In particular, drug development initiatives have centred on the melanocortin system [295], encouraged by the human genetic data reviewed above, and several nonpeptide compounds are now being tested in a clinical setting [22]. The cannabinoid system also provides an attractive target, with promising early results with the inverse CB1 receptor agonist, rimonabant [296], currently in phase III clinical trial. Initial evaluations suggest that rimonabant decreases body weight by ca 510%, with benecial effects also on insulin resistance and dyslipidaemia [292]. Interestingly, this drug has the added benet of facilitating smoke cessation. However, the full safety prole of rimonabant has not yet been released. Conversely, the active component of marijuana, D9-tetrahydrocannabinol, is also being evaluated for treatment of AIDS-associated anorexia [297]. Early hopes for a leptin-based obesity regimen were quelled by clinical trials showing only very limited weight loss following leptin administration to obese subjects [298], and there are also indications that such treatment may in itself produce the leptin resistance hypothesized to be a part of obesity [299]. It should be pointed out, however, that in the rare cases of genetic leptin-deciency, treatment with recombinant leptin has virtually normalized body weight in near-fatally obese children, whilst simultaneously inducing age-appropriate puberty [300] (Fig. 9). The same treatment has also been used to
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successfully rectify several of the metabolic abnormalities associated with lipodystrophy [301, 302]. Furthermore, pertaining to a not uncommon diagnosis, leptin treatment has recently been demonstrated as a highly promising therapy for functional amenorrhoea [303].
Conclusion
In summary, signicant advances in our understanding of feeding behaviour have been achieved using a combination of clinical, behavioural, electrophysiological, anatomical, genetic and imaging techniques. This investigation has dened an underlying circuitry and neuropharmacology, which can now be probed for therapeutic targets. Thus, whilst many questions remain to be answered, in particular regarding the causal mechanisms of obesity and anorexia as well as the central circuitry bridging metabolic input and output, there is reason for hope in offering effective treatments for these exceptionally common and debilitating disorders.
Conict of interest statement

No conict of interest was declared.
Acknowledgements
The author gratefully acknowledges generous nancial support from Wenner-Gren Stiftelserna, Vet enskapsradet, Jeanssons Stiftelser, Hagbergs Stiftelse, Rut och Arvid Wolffs Stiftelse, Thurings Stiftelse, Svenska Lakaresa llskapet, Ake Wibergs Stiftelse, Kgl. Vetenskapsakademien, Hedlunds Stiftelse, Magnus Bergvalls Stiftelse, Lars Hiertas Minne, Axel Linders Stiftelse, Langmanska Kulturfonden, Teodor Neran ders Fond and internal funds of Karolinska Institutet.
References
1 Galbraith JK. The New Industrial State. Boston, MA: Houghton Mifin, 1967. 2 World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Geneva: World Health Organization, 2000. 3 National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000; 160: 898904. 4 World Health Organization. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003; 916: iviii, 1149, backcover.
5 Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE, Willett WC. Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med 1989; 321: 5639. 6 Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988; 109: 1824. 7 Grodstein F, Goldman MB, Cramer DW. Body mass index and ovulatory infertility. Epidemiology 1994; 5: 24750. 8 Rexrode KM, Hennekens CH, Willett WC et al. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 1997; 277: 153945. 9 Scheinfeld NS. Obesity and dermatology. Clin Dermatol 2004; 22: 3039. 10 Gottschlich MM, Mayes T, Khoury JC, Warden GD. Signicance of obesity on nutritional, immunologic, hormonal, and clinical outcome parameters in burns. J Am Diet Assoc 1993; 93: 12618. 11 Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999; 341: 1097105. 12 Puhl R, Brownell KD. Bias, discrimination, and obesity. Obes Res 2001; 9: 788805. 13 Pontiroli AE. Type 2 diabetes mellitus is becoming the most common type of diabetes in school children. Acta Diabetol 2004; 41: 8590. 14 Hoek HW, van Hoeken D. Review of the prevalence and incidence of eating disorders. Int J Eat Disord 2003; 34: 383 96. 15 Plata-Salaman CR. Cytokines and feeding. News Physiol Sci 1998; 13: 298304. 16 Strasser F, Bruera ED. Update on anorexia and cachexia. Hematol Oncol Clin North Am 2002; 16: 589617. 17 Briefel RR, McDowell MA, Alaimo K et al. Total energy intake of the US population: the third National Health and Nutrition Examination Survey, 19881991. Am J Clin Nutr 1995; 62: 1072S80S. 18 Johnson D, Drenick EJ. Therapeutic fasting in morbid obesity. Arch Intern Med 1977; 137: 13812. 19 Mitchel JS, Keesey RE. Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: evidence from a restriction-refeeding regimen. Physiol Behav 1977; 18: 11215. 20 Sims EA, Danforth E Jr, Horton ES, Bray GA, Glennon JA, Salans LB. Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 1973; 29: 45796. 21 Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by progress? Am J Hum Genet 1962; 14: 353 62. 22 Farrigan C, Pang K. Obesity market overview. Nat Rev Drug Discov 2002; 1: 2578. 23 Sjostrom L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 268393. 24 Bergh C, Brodin U, Lindberg G, Sodersten P. Randomized controlled trial of a treatment for anorexia and bulimia nervosa. Proc Natl Acad Sci U S A 2002; 99: 948691. 25 Mohr B. Hypertrophie der Hypophysis cerebri und adurch bedingter Druck auf die Hirngrundache, ins besondere auf die Sehnerven, das Chiasma derselben und den linkseitigen Hirnschenkel. Wschr ges Heilk 1840; 6: 56571.
320
C. BROBERGER
26 Babinski MJ. Tumeur du corps pituitaire sans acromegalie et avec arret de developpement des organes genitaux. Rev Neurol 1900; 8: 5313. 27 Frohlich A. Ein Fall von Tumor der Hypophysis cerebri ohne Akromegalie. Wien Klin Rundschau 1901; 15: 8836, 906 8. 28 Bray GA, Gallagher TF Jr. Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 1975; 54: 30130. 29 Aschner B. Uber die funktion der hypophyse. Arch f d ges Physiol 1912; 146: 1146. 30 Hetherington AW, Ranson SW. Hypothalamic lesions and adiposity in the rat. Anat Rec 1940; 78: 14972. 31 Anand BK, Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med 1951; 24: 12340. 32 Anand BK, Brobeck JR. Localization of a feeding center in the hypothalamus of the rat. Proc Soc Exp Biol Med 1951; 77: 3234. 33 Grill HJ, Norgren R. Chronically decerebrate rats demonstrate satiation but not bait shyness. Science 1978; 201: 2679. 34 Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci 1953; 140: 57896. 35 MacLagan NF. The role of appetite in the control of body weight. J Physiol 1937; 90: 38594. 36 Stellar E. The physiology of motivation. Psychol Rev 1954; 61: 522. 37 Berthoud HR. Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 2002; 26: 393428. 38 Grill HJ, Kaplan JM. The neuroanatomical axis for control of energy balance. Front Neuroendocrinol 2002; 23: 240. 39 Khosla T, Billewicz WZ. Measurement of change in bodyweight. Br J Nutr 1964; 18: 22739. 40 Broberger C, Hokfelt T. Hypothalamic and vagal neuropep tide circuitries regulating food intake. Physiol Behav 2001; 74: 66982. ` 41 Ramon y Cajal S. Histologie du systeme nerveux de lhomme et des vertebres. Oxford: Oxford University Press (republ. 1995), 1909. 42 Harding R, Leek BF. Central projections of gastric afferent vagal inputs. J Physiol 1973; 228: 7390. 43 Appleyard SM, Bailey TW, Doyle MW et al. Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. J Neurosci 2005; 25: 357885. 44 Swanson LW, Mogenson GJ. Neural mechanisms for the functional coupling of autonomic, endocrine and somatomotor responses in adaptive behavior. Brain Res 1981; 228: 134. 45 Smith GP. The direct and indirect controls of meal size. Neurosci Biobehav Rev 1996; 20: 416. 46 Sclafani A, Ackroff K, Schwartz GJ. Selective effects of vagal deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal nutrients. Physiol Behav 2003; 78: 28594. 47 Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973; 84: 488 95. 48 Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ. Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 1981; 213: 10367.
49 Schwartz GJ, McHugh PR, Moran TH. Integration of vagal afferent responses to gastric loads and cholecystokinin in rats. Am J Physiol Regul Integr Comp Physiol 1991; 261: R649. 50 Schwartz GJ, McHugh PR, Moran TH. Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents. Am J Physiol Regul Integr Comp Physiol 1993; 265: R8726. 51 Sykes RM, Spyer KM, Izzo PN. Demonstration of glutamate immunoreactivity in vagal sensory afferents in the nucleus tractus solitarius of the rat. Brain Res 1997; 762: 111. 52 Broberger C, Holmberg K, Kuhar MJ, Hokfelt T. Cocaine- and amphetamine-regulated transcript in the rat vagus nerve: a putative mediator of cholecystokinin-induced satiety. Proc Natl Acad Sci U S A 1999; 96: 1350611. 53 Aja S, Schwartz GJ, Kuhar MJ, Moran TH. Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure. Am J Physiol Regul Integr Comp Physiol 2001; 280: R16139. 54 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 42532. 55 Ahima RS, Prabakaran D, Mantzoros C et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 2502. 56 Halaas JL, Gajiwala KS, Maffei M et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 5436. 57 Maffei M, Halaas J, Ravussin E et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155 61. 58 Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: 33750. 59 Cohen P, Zhao C, Cai X et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 2001; 108: 111321. 60 Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 1979; 282: 5035. 61 Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 2002; 5: 56672. 62 Nicoladis S, Rowland N. Metering of intravenous versus oral nutrients and regulation of energy balance. Am J Physiol 1976; 231: 6618. 63 Woods SC, Stein LJ, McKay LD, Porte D Jr. Suppression of food intake by intravenous nutrients and insulin in the baboon. Am J Physiol 1984; 247: R393401. 64 Parra-Covarrubias A, Rivera-Rodriguez I, Almaraz-Ugalde A. Cephalic phase of insulin secretion in obese adolescents. Diabetes 1971; 20: 8002. 65 Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8: 137682. 66 Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab 2005; 1: 53 61. 67 Strader AD, Woods SC. Gastrointestinal hormones and food intake. Gastroenterology 2005; 128: 17591.
321
68 Lundberg JM, Tatemoto K, Terenius L et al. Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood ow and motility. Proc Natl Acad Sci U S A 1982; 79: 44715. 69 Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985; 89: 10707. 70 Adrian TE, Bacarese-Hamilton AJ, Smith HA, Chohan P, Manolas KJ, Bloom SR. Distribution and postprandial release of porcine peptide YY. J Endocrinol 1987; 113: 1114. 71 Greeley GH Jr, Hashimoto T, Izukura M et al. A comparison of intraduodenally and intracolonically administered nutrients on the release of peptide-YY in the dog. Endocrinology 1989; 125: 17615. 72 Morley JE, Flood JF. An investigation of tolerance to the actions of leptogenic and anorexigenic drugs in mice. Life Sci 1987; 41: 215765. 73 Batterham RL, Cowley MA, Small CJ et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002; 418: 6504. 74 Tschop M, Castaneda TR, Joost HG et al. Physiology: does gut hormone PYY3-36 decrease food intake in rodents? Nature 2004, 430: 165. 75 Batterham RL, Cowley MA, Small CJ et al. Physiology: does gut hormone PYY3-36 decrease food intake in rodents? (reply). Nature 2004; 430: 165. 76 Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 2004; 145: 258590. 77 Pittner RA, Moore CX, Bhavsar SP et al. Effects of PYY[3-36] in rodent models of diabetes and obesity. Int J Obes Relat Metab Disord 2004; 28: 96371. 78 Batterham RL, Bloom SR. The gut hormone peptide YY regulates appetite. Ann N Y Acad Sci 2003; 994: 1628. 79 Imamura M, Takahashi H, Mikami Y, Yamauchi H. Elevation of plasma peptide YY and pancreatic juice hypersecretion following massive small bowel resection in the rat. Tohoku J Exp Med 1998; 184: 4959. 80 Adrian TE, Savage AP, Fuessl HS, Wolfe K, Besterman HS, Bloom SR. Release of peptide YY (PYY) after resection of small bowel, colon, or pancreas in man. Surgery 1987; 101: 7159. 81 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 65660. 82 Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005; 85: 495522. 83 Wren AM, Small CJ, Ward HL et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 43258. 84 Wren AM, Small CJ, Abbott CR et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 25407. 85 Nakazato M, Murakami N, Date Y et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409: 1948. 86 Tschop M, Weyer C, Tataranni PA, Devanarayan V, Rav ussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 7079. 87 Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels
88
89
90
91
92
93
94
95 96 97
98
99
100
101 102
103
104
105
106
suggests a role in meal initiation in humans. Diabetes 2001; 50: 17149. Masuda Y, Tanaka T, Inomata N et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 9058. Date Y, Murakami N, Toshinai K et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002; 123: 11208. Wang L, Saint-Pierre DH, Tache Y. Peripheral ghrelin selectively increases Fos expression in neuropeptide Y-synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci Lett 2002; 325: 4751. Shintani M, Ogawa Y, Ebihara K et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 2001; 50: 22732. Lu S, Guan JL, Wang QP et al. Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci Lett 2002; 321: 15760. Cowley MA, Smith RG, Diano S et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 64961. Naslund E, Hellstrom PM, Kral JG. The gut and food intake: an update for surgeons. J Gastrointest Surg 2001; 5: 55667. Mason EE, Ito C. Gastric bypass in obesity. Surg Clin North Am 1967; 47: 134551. Halmi KA, Mason E, Falk JR, Stunkard A. Appetitive behavior after gastric bypass for obesity. Int J Obes 1981; 5: 45764. Cummings DE, Weigle DS, Frayo RS et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 162330. Cummings DE, Clement K, Purnell JQ et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002; 8: 6434. Hollister LE. Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. Clin Pharmacol Ther 1971; 12: 4449. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association, 1994. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003; 4: 87384. Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1999; 143: 3157. Berry EM, Mechoulam R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol Ther 2002; 95: 18590. Rodriguez de Fonseca F, Navarro M, Gomez R et al. An anorexic lipid mediator regulated by feeding. Nature 2001; 414: 20912. Gaetani S, Cuomo V, Piomelli D. Anandamide hydrolysis: a new target for anti-anxiety drugs? Trends Mol Med 2003; 9: 4748. Guzman M, Lo Verme J, Fu J, Oveisi F, Blazquez C, Piomelli D. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem 2004; 279: 2784954.
322
C. BROBERGER
107 Fu J, Gaetani S, Oveisi F et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 2003; 425: 903. 108 Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347: 64550. 109 Schwartz MW, Marks JL, Sipols AJ et al. Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology 1991; 128: 26457. 110 Schwartz MW, Seeley RJ, Woods SC et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46: 211923. 111 Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997; 138: 50636. 112 Kim EM, Grace MK, Welch CC, Billington CJ, Levine AS. STZinduced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats. Am J Physiol 1999; 276: R13206. 113 Elias CF, Aschkenasi C, Lee C et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999; 23: 77586. 114 Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA. Neuronal glucosensing: what do we know after 50 years? Diabetes 2004; 53: 25218. 115 Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATPsensitive potassium channels. Nature 1997; 390: 5215. 116 Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 2000; 3: 7578. 117 Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 2001; 413: 7945. 118 Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain. Brain Res 1998; 814: 4154. 119 Ibrahim N, Bosch MA, Smart JL et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 2003; 144: 1331 40. 120 Wang R, Liu X, Hentges ST et al. The regulation of glucoseexcited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 2004; 53: 195965. 121 Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 2003; 9: 75661. 122 Pocai A, Lam TK, Gutierrez-Juarez R et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005; 434: 102631. 123 Coppari R, Ichinose M, Lee CE et al. The hypothalamic arcuate nucleus: a key site for mediating leptins effects on glucose homeostasis and locomotor activity. Cell Metab 2005; 1: 6372. 124 Stanley BG, Magdalin W, Seira A, Thomas WJ, Leibowitz SF. The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res 1993; 604: 30417.
125 Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996; 381: 41521. 126 Bannon AW, Seda J, Carmouche M et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res 2000; 868: 7987. 127 Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996; 274: 17047. 128 Lin S, Boey D, Herzog H. NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides 2004; 38: 189200. 129 McCrea K, Wisialowski T, Cabrele C et al. 236[K4, RYYSA(1923)]PP a novel Y5-receptor preferring ligand with strong stimulatory effect on food intake. Regul Pept 2000; 87: 4758. 130 Ammar AA, Sederholm F, Saito TR, Scheurink AJ, Johnson AE, Sodersten P. NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior. Am J Physiol Regul Integr Comp Physiol 2000; 278: R1627 33. 131 Poggioli R, Vergoni AV, Bertolini A. ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists. Peptides 1986; 7: 8438. 132 Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 1658. 133 Huszar D, Lynch CA, Fairchild-Huntress V et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 13141. 134 Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deciency responds to peripheral melanocortin. Nat Med 1999; 5: 106670. 135 Butler AA, Kesterson RA, Khong K et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptordecient mouse. Endocrinology 2000; 141: 351821. 136 Butler AA, Marks DL, Fan W, Kuhn CM, Bartolome M, Cone RD. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 2001; 4: 60511. 137 Swanson LW, Kuypers HG. The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde uorescence double-labeling methods. J Comp Neurol 1980; 194: 55570. 138 Cechetto DF, Saper CB. Neurochemical organization of the hypothalamic projection to the spinal cord in the rat. J Comp Neurol 1988; 272: 579604. 139 Elias CF, Lee C, Kelly J et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21: 137585. 140 Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, ORahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348: 108595. 141 Ollmann MM, Wilson BD, Yang YK et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 1358. 142 Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T. Hypocretin/ orexin- and melanin-concentrating hormone-expressing
323
143
144
145
146
147
148
149
150
151 152
153
154
155
156
157
158
cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 1998; 402: 46074. Hahn TM, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998; 1: 2712. Hagan MM, Rushing PA, Pritchard LM et al. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol Regul Integr Comp Physiol 2000; 279: R4752. Csiffary A, Gorcs TJ, Palkovits M. Neuropeptide Y innervation of ACTH-immunoreactive neurons in the arcuate nucleus of rats: a correlated light and electron microscopic double immunolabeling study. Brain Res 1990; 506: 21522. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 1997; 66: 393408. Roseberry AG, Liu H, Jackson AC, Cai X, Friedman JM. Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 2004; 41: 71122. Dumont Y, Fournier A, St-Pierre S, Quirion R. Characterization of neuropeptide Y binding sites in rat brain membrane preparations using [125I][Leu31, Pro34]peptide YY and [125I]peptide YY3-36 as selective Y1 and Y2 radioligands. J Pharmacol Exp Ther 1995; 272: 67380. Decavel C, Van den Pol AN. GABA: a dominant neurotransmitter in the hypothalamus. J Comp Neurol 1990; 302: 101937. van den Pol AN, Wuarin JP, Dudek FE. Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science 1990; 250: 12768. van den Pol AN. Weighing the role of hypothalamic feeding neurotransmitters. Neuron 2003; 40: 105961. Hokfelt T, Johansson O, Ljungdahl A, Lundberg JM, Schultzberg M. Peptidergic neurones. Nature 1980; 284: 51521. Stanley BG, Willett VL, III, Donias HW, Ha LH, Spears LC. The lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating. Brain Res 1993; 630: 419. Stanley BG, Willett VL, III, Donias HW, Dee MG, II, Duva MA. Lateral hypothalamic NMDA receptors and glutamate as physiological mediators of eating and weight control. Am J Physiol 1996; 270: R4439. Horvath TL, Bechmann I, Naftolin F, Kalra SP, Leranth C. Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 1997; 756: 2836. Collin M, Backberg M, Ovesjo ML et al. Plasma membrane and vesicular glutamate transporter mRNAs/proteins in hypothalamic neurons that regulate body weight. Eur J Neurosci 2003; 18: 126578. Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 1999; 24: 15563. Pronchuk N, Beck-Sickinger AG, Colmers WF. Multiple NPY receptors inhibit GABA(A) synaptic responses of rat medial
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
parvocellular effector neurons in the hypothalamic paraventricular nucleus. Endocrinology 2002; 143: 53543. Wahlestedt C, Yanaihara N, Hakanson R. Evidence for different pre- and post-junctional receptors for neuropeptide Y and related peptides. Regul Pept 1986; 13: 30718. Kopp J, Xu ZQ, Zhang X et al. Expression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization. Neuroscience 2002; 111: 443532. Elias CF, Saper CB, Maratos-Flier E et al. Chemically dened projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 1998; 402: 442 59. Peyron C, Tighe DK, van den Pol AN et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18: 999610015. Chemelli RM, Willie JT, Sinton CM et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 43751. Lin L, Faraco J, Li R et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 36576. Peyron C, Faraco J, Rogers W et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6: 9917. Thannickal TC, Moore RY, Nienhuis R et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 46974. Verret L, Goutagny R, Fort P et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 2003; 4: 19. Fu LY, Acuna-Goycolea C, van den Pol AN. Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci 2004; 24: 874151. van den Pol AN, Acuna-Goycolea C, Clark KR, Ghosh PK. Physiological properties of hypothalamic MCH neurons identied with selective expression of reporter gene after recombinant virus infection. Neuron 2004; 42: 63552. Campbell RE, Smith MS, Allen SE, Grayson BE, FfrenchMullen JM, Grove KL. Orexin neurons express a functional pancreatic polypeptide Y4 receptor. J Neurosci 2003; 23: 148797. Turek FW, Joshu C, Kohsaka A et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005; 308: 10435. Kreier F, Yilmaz A, Kalsbeek A et al. Hypothesis: shifting the equilibrium from activity to food leads to autonomic unbalance and the metabolic syndrome. Diabetes 2003; 52: 26526. Buijs RM, la Fleur SE, Wortel J et al. The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons. J Comp Neurol 2003; 464: 3648. Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 1972; 42: 2016. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 1972; 69: 15836.
324
C. BROBERGER
176 Kreier F, Fliers E, Voshol PJ et al. Selective parasympathetic innervation of subcutaneous and intra-abdominal fat functional implications. J Clin Invest 2002; 110: 124350. 177 Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med 2001; 58: 74752. 178 Sekine M, Yamagami T, Handa K et al. A dose-response relationship between short sleeping hours and childhood obesity: results of the Toyama Birth Cohort Study. Child Care Health Dev 2002; 28: 16370. 179 Sinha MK, Ohannesian JP, Heiman ML et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 1996; 97: 13447. 180 Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4: 2034. 181 Davis JD, Smith GP. Learning to sham feed: behavioral adjustments to loss of physiological postingestional stimuli. Am J Physiol 1990; 259: R122835. 182 Schwartz GJ, Salorio CF, Skoglund C, Moran TH. Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression. Am J Physiol 1999; 276: R16239. 183 Erdheim J. Uber Hypophysengangsgeschwulste und Hirn cholesteatome. Sitzungsb d k Akad d Wissensch Math-naturw Cl Wien 1904; 113: 537726. 184 Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969; 164: 71921. 185 Bugarith K, Dinh TT, Li AJ, Speth RC, Ritter S. Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake. Endocrinology 2005; 146: 117991. 186 Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 2002; 143: 23946. 187 Hosoi T, Kawagishi T, Okuma Y, Tanaka J, Nomura Y. Brain stem is a direct target for leptins action in the central nervous system. Endocrinology 2002; 143: 3498504. 188 Huo L, Grill HJ, Bjorbaek C. Leptin-dependent activation of STAT3 phosphorylation in the medial sub-nucleus of the nucleus of the solitary tract (NTS) and regulation of proopiomelanocortin (POMC), pro-glucagon and galanin-likepeptide (GALP) mRNA. In Endocrine Society Proceedings, San Francisco, CA, USA, 2005. 189 Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM. Brainstem application of melanocortin receptor ligands produces longlasting effects on feeding and body weight. J Neurosci 1998; 18: 1012835. 190 Fan W, Ellacott KL, Halatchev IG, Takahashi K, Yu P, Cone RD. Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci 2004; 7: 3356. 191 Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ. Hyperphagic effects of brainstem ghrelin administration. Diabetes 2003; 52: 22605. 192 Mizuno Y, Oomura Y. Glucose responding neurons in the nucleus tractus solitarius of the rat: in vitro study. Brain Res 1984; 307: 10916.
193 Morton GJ, Blevins JE, Williams DL et al. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 2005; 115: 70310. 194 Eskay RL, Giraud P, Oliver C, Brown-Stein MJ. Distribution of alpha-melanocyte-stimulating hormone in the rat brain: evidence that alpha-MSH-containing cells in the arcuate region send projections to extrahypothalamic areas. Brain Res 1979; 178: 5567. 195 Sim LJ, Joseph SA. Arcuate nucleus projections to brainstem regions which modulate nociception. J Chem Neuroanat 1991; 4: 97109. 196 Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A 1998; 95: 150438. 197 Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 2004; 24: 2797 805. 198 Saper CB. Organization of cerebral cortical afferent systems in the rat. II. Hypothalamocortical projections. J Comp Neurol 1985; 237: 2146. 199 Kishi T, Aschkenasi CJ, Choi BJ et al. Neuropeptide Y Y1 receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor. J Comp Neurol 2005; 482: 21743. 200 Norgren R. Projections from the nucleus of the solitary tract in the rat. Neuroscience 1978; 3: 20718. 201 Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res 1978; 153: 126. 202 ter Horst GJ, de Boer P, Luiten PG, van Willigen JD. Ascending projections from the solitary tract nucleus to the hypothalamus. A Phaseolus vulgaris lectin tracing study in the rat. Neuroscience 1989; 31: 78597. 203 DeFalco J, Tomishima M, Liu H et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 2001; 291: 260813. 204 McCormick DA. Cortical and subcortical generators of normal and abnormal rhythmicity. Int Rev Neurobiol 2002; 49: 99114. 205 Thompson RH, Swanson LW. Structural characterization of a hypothalamic visceromotor pattern generator network. Brain Res Brain Res Rev 2003; 41: 153202. 206 Swanson LW. Cerebral hemisphere regulation of motivated behavior. Brain Res 2000; 886: 11364. 207 Choi GB, Dong HW, Murphy AJ et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 2005; 46: 647 60. 208 Bargmann W. Uber die neurosekretorische verknupfung von hypothalamus und neurohypophyse. Z Zellforsch Mikr 1949; 34: 61034. 209 Saper CB, Loewy AD, Swanson LW, Cowan WM. Direct hypothalamo-autonomic connections. Brain Res 1976; 117: 30512. 210 Swanson LW, Sawchenko PE. Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 1983; 6: 269324.
325
211 Hodgkin J, Doniach T. Natural variation and copulatory plug formation in Caenorhabditis elegans. Genetics 1997; 146: 14964. 212 de Bono M, Bargmann CI. Natural variation in a neuropeptide Y receptor homolog modies social behavior and food response in C. elegans. Cell 1998; 94: 67989. 213 de Bono M. Molecular approaches to aggregation behavior and social attachment. J Neurobiol 2003; 54: 7892. 214 Rogers C, Reale V, Kim K et al. Inhibition of Caenorhabditis elegans social feeding by FMRFamide-related peptide activation of NPR-1. Nat Neurosci 2003; 6: 117885. 215 Cheung BH, Arellano-Carbajal F, Rybicki I, de Bono M. Soluble guanylate cyclases act in neurons exposed to the body uid to promote C. elegans aggregation behavior. Curr Biol 2004; 14: 110511. 216 Gray JM, Karow DS, Lu H et al. Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 2004; 430: 31722. 217 Teyke T, Weiss KR, Kupfermann I. An identied neuron (CPR) evokes neuronal responses reecting food arousal in Aplysia. Science 1990; 247: 857. 218 Kupfermann I. Feeding behavior in Aplysia: a simple system for the study of motivation. Behav Biol 1974; 10: 126. 219 Hurwitz I, Kupfermann I, Susswein AJ. Different roles of neurons B63 and B34 that are active during the protraction phase of buccal motor programs in Aplysia californica. J Neurophysiol 1997; 78: 130519. 220 Blumberg S, Susswein AJ. Consummatory feeding movements in Aplysia fasciata are facilitated by conspecics with access to mates, by reproductive tract homogenates and by bag cell peptides. J Comp Physiol 1998; 182: 175 82. 221 Del Parigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA. Are we addicted to food? Obes Res 2003; 11: 4935. 222 Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988; 85: 52748. 223 Zhou QY, Palmiter RD. Dopamine-decient mice are severely hypoactive, adipsic, and aphagic. Cell 1995; 83: 1197209. 224 Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004; 65 (Suppl. 18): 1326. 225 Saper CB, Chou TC, Elmquist JK. The need to feed: homeostatic and hedonic control of eating. Neuron 2002; 36: 199 211. 226 Baldo BA, Sadeghian K, Basso AM, Kelley AE. Effects of selective dopamine D1 or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity. Behav Brain Res 2002; 137: 165 77. 227 Kelley AE. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobehav Rev 2004; 27: 76576. 228 Kelley AE, Will MJ, Steininger TL, Zhang M, Haber SN. Restricted daily consumption of a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin gene expression. Eur J Neurosci 2003; 18: 25928. 229 Zhang M, Gosnell BA, Kelley AE. Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens. J Pharmacol Exp Ther 1998; 285: 90814.
230 Will MJ, Franzblau EB, Kelley AE. The amygdala is critical for opioid-mediated binge eating of fat. Neuroreport 2004; 15: 185760. 231 Balleine BW, Killcross AS, Dickinson A. The effect of lesions of the basolateral amygdala on instrumental conditioning. J Neurosci 2003; 23: 66675. 232 Maldonado-Irizarry CS, Swanson CJ, Kelley AE. Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus. J Neurosci 1995; 15: 677988. 233 Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol 1980; 14: 6997. 234 Risold PY, Thompson RH, Swanson LW. The structural organization of connections between hypothalamus and cerebral cortex. Brain Res Brain Res Rev 1997; 24: 197 254. 235 Rolls ET. Smell, taste, texture, and temperature multimodal representations in the brain, and their relevance to the control of appetite. Nutr Rev 2004; 62: S193204; discussion: S224141. 236 Cechetto DF, Saper CB. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J Comp Neurol 1987; 262: 2745. 237 Yaxley S, Rolls ET, Sienkiewicz ZJ. The responsiveness of neurons in the insular gustatory cortex of the macaque monkey is independent of hunger. Physiol Behav 1988; 42: 2239. 238 Rolls ET, Baylis LL. Gustatory, olfactory, and visual convergence within the primate orbitofrontal cortex. J Neurosci 1994; 14: 543752. 239 Kringelbach ML, ODoherty J, Rolls ET, Andrews C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb Cortex 2003; 13: 106471. 240 Tataranni PA, Gautier JF, Chen K et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999; 96: 456974. 241 DelParigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA. Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast. Neuroimage 2005; 24: 43643. 242 DelParigi A, Chen K, Salbe AD et al. Persistence of abnormal neural responses to a meal in postobese individuals. Int J Obes Relat Metab Disord 2004; 28: 3707. 243 Kagotani Y, Hashimoto T, Tsuruo Y, Kawano H, Daikoku S, Chihara K. Development of the neuronal system containing neuropeptide Y in the rat hypothalamus. Int J Dev Neurosci 1989; 7: 35974. 244 Grove KL, Smith MS. Ontogeny of the hypothalamic neuropeptide Y system. Physiol Behav 2003; 79: 4763. 245 Cramer CP, Blass EM. Nutritive and nonnutritive determinants of milk intake of suckling rats. Behav Neurosci 1985; 99: 57882. 246 Broberger C, Johansen J, Schalling M, Hokfelt T. Hypotha lamic neurohistochemistry of the murine anorexia (anx/ anx) mutation: altered processing of neuropeptide Y in the arcuate nucleus. J Comp Neurol 1997; 387: 12435. 247 Broberger C, Johansen J, Brismar H, Johansson C, Schalling M, Hokfelt T. Changes in neuropeptide Y receptors and
326
C. BROBERGER
248
249
250
251
252
253
254
255
256
257
258
259 260
261
262
263
264
pro-opiomelanocortin in the anorexia (anx/anx) mouse hypothalamus. J Neurosci 1999; 19: 71309. Singer LK, Kuper J, Brogan RS, Smith MS, Grove KL. Novel expression of hypothalamic neuropeptide Y during postnatal development in the rat. Neuroreport 2000; 11: 107580. Mistry AM, Swick A, Romsos DR. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am J Physiol 1999; 277: R7427. Hayashida T, Nakahara K, Mondal MS et al. Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol 2002; 173: 23945. Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 1998; 101: 10207. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304: 10810. Levin BE, Govek E. Gestational obesity accentuates obesity in obesity-prone progeny. Am J Physiol 1998; 275: R13749. Dabelea D, Hanson RL, Lindsay RS et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000; 49: 220811. Grove KL, Williams SM, Xiao XQ, Smith MS. Fetal metabolic adaptations in nonhuman primates (NHP): effects of dietinduced gestational hyperinsulinemia and hyperleptinemia. In Endocrine Society Proceedings, San Francisco, CA, USA, 2005. Gruenewald DA, Naai MA, Marck BT, Matsumoto AM. Agerelated decrease in neuropeptide-Y gene expression in the arcuate nucleus of the male rat brain is independent of testicular feedback. Endocrinology 1994; 134: 23839. Gruenewald DA, Matsumoto AM. Age-related decrease in proopiomelanocortin gene expression in the arcuate nucleus of the male rat brain. Neurobiol Aging 1991; 12: 11321. Leal S, Andrade JP, Paula-Barbosa MM, Madeira MD. Arcuate nucleus of the hypothalamus: effects of age and sex. J Comp Neurol 1998; 401: 6588. Langhans W. Anorexia of infection: current prospects. Nutrition 2000; 16: 9961005. von Meyenburg C, Hrupka BH, Arsenijevic D, Schwartz GJ, Landmann R, Langhans W. Role for CD14, TLR2, and TLR4 in bacterial product-induced anorexia. Am J Physiol Regul Integr Comp Physiol 2004; 287: R298305. Bret-Dibat JL, Bluthe RM, Kent S, Kelley KW, Dantzer R. Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun 1995; 9: 2426. Cao C, Matsumura K, Yamagata K, Watanabe Y. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response. Brain Res 1995; 697: 18796. Lugarini F, Hrupka BJ, Schwartz GJ, Plata-Salaman CR, Langhans W. A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats. Am J Physiol Regul Integr Comp Physiol 2002; 283: R8628. von Meyenburg C, Langhans W, Hrupka BJ. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia. Pharmacol Biochem Behav 2003; 74: 102531.
265 Waldbillig RJ, Bartness TJ, Stanley BG. Increased food intake, body weight, and adiposity in rats after regional neurochemical depletion of serotonin. J Comp Physiol Psychol 1981; 95: 391405. 266 Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptinindependent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 1998; 4: 11526. 267 Heisler LK, Cowley MA, Tecott LH et al. Activation of central melanocortin pathways by fenuramine. Science 2002; 297: 60911. 268 Madej T, Boguski MS, Bryant SH. Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett 1995; 373: 138. 269 Baumann H, Morella KK, White DW et al. The full-length leptin receptor has signaling capabilities of interleukin 6type cytokine receptors. Proc Natl Acad Sci U S A 1996; 93: 83748. 270 Evans WK, Makuch R, Clamon GH et al. Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer. Cancer Res 1985; 45: 334753. 271 Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer 1974; 33: 56873. 272 Tisdale MJ. Tumor-host interactions. J Cell Biochem 2004; 93: 8717. 273 Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale M. Characterization of a cancer cachectic factor. Nature 1996; 379: 73942. 274 Lorite MJ, Smith HJ, Arnold JA, Morris A, Thompson MG, Tisdale MJ. Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF). Br J Cancer 2001; 85: 297302. 275 Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res 2001; 61: 36049. 276 Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The effect of an oral nutritional supplement enriched with sh oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999; 81: 806. 277 Olden K, Wilson S. Environmental health and genomics: visions and implications. Nat Rev Genet 2000; 1: 14953. 278 Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC, Hayakawa K. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord 1996; 20: 5016. 279 Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med 1990; 322: 14837. 280 Friedman JM. A war on obesity, not the obese. Science 2003; 299: 8568. 281 Ravussin E, Bogardus C. Energy balance and weight regulation: genetics versus environment. Br J Nutr 2000; 83 (Suppl. 1): S1720. 282 Montague CT, Farooqi IS, Whitehead JP et al. Congenital leptin deciency is associated with severe early-onset obesity in humans. Nature 1997; 387: 9038. 283 Clement K, Vaisse C, Lahlou N et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398401.
327
284 Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufciency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 1557. 285 Jackson RS, Creemers JW, Ohagi S et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16: 3036. 286 Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, ORahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20: 1112. 287 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106: 25362. 288 Hinney A, Hohmann S, Geller F et al. Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test conrm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab 2003; 88: 425867. 289 Jacobson P, Ukkola O, Rankinen T et al. Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. J Clin Endocrinol Metab 2002; 87: 44426. 290 Galuska DA, Will JC, Serdula MK, Ford ES. Are health care professionals advising obese patients to lose weight? JAMA 1999; 282: 15768. 291 Wee CC, McCarthy EP, Davis RB, Phillips RS. Physician counseling about exercise. JAMA 1999; 282: 15838. 292 Fong TM. Advances in anti-obesity therapeutics. Expert Opin Investig Drugs 2005; 14: 24350. 293 Raisch DW, Fye CL, Boardman KD, Sather MR. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother 2002; 36: 31221. 294 Jones RM, Boatman PD, Semple G, Shin YJ, Tamura SY. Clinically validated peptides as templates for de novo peptidomimetic drug design at G-protein-coupled receptors. Curr Opin Pharmacol 2003; 3: 53043.
295 MacNeil DJ, Howard AD, Guan X et al. The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur J Pharmacol 2002; 450: 93109. 296 Chen RZ, Huang RR, Shen CP, MacNeil DJ, Fong TM. Synergistic effects of cannabinoid inverse agonist AM251 and opioid antagonist nalmefene on food intake in mice. Brain Res 2004; 999: 22730. 297 Beal JE, Olson R, Laubenstein L et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995; 10: 8997. 298 Heymseld SB, Greenberg AS, Fujioka K et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 282: 1568 75. 299 Montez JM, Soukas A, Asilmaz E, Fayzikhodjaeva G, Fantuzzi G, Friedman JM. Acute leptin deciency, leptin resistance, and the physiologic response to leptin withdrawal. Proc Natl Acad Sci U S A 2005; 102: 253742. 300 Farooqi IS, Matarese G, Lord GM et al. Benecial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deciency. J Clin Invest 2002; 110: 1093103. 301 Oral EA, Simha V, Ruiz E et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346: 5708. 302 Javor ED, Ghany MG, Cochran EK et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005; 41: 75360. 303 Welt CK, Chan JL, Bullen J et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351: 98797. 304 Del Parigi A, Gautier JF, Chen K et al. Neuroimaging and obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography. Ann N Y Acad Sci 2002; 967: 38997. Correspondence: Christian Broberger MD, PhD, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. (fax: +468 33 16 92; e-mail: christian.broberger@neuro.ki.se).

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Journal of Internal Medicine 2005; 258: 301327

Brain regulation of food intake and appetite: molecules and networks

A central framework for sensing and orchestrating energy metabolism

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

NPY POMC ARC

Peripheral control of feeding behaviour

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

Integration of peripheral signals in the Arc

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

Cerebral Cor tex

Endocrine regulation incl. thyroid and adrenocortical axes

Sympathetic ANS Parasympathetic

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

Contributions of hind- and forebrain to feeding regulation

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

Food intake in lower organisms: models for the organization of behaviour

Food reward: role of the nucleus accumbens

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

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Firing rate (spikes s1)

Spontaneous 10 Behavioural response to satiating food +2 +1 0 -1 -2

Volume of 20% blackcurrant juice

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

Development of the feeding circuitry

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

Mechanisms of anorexia in infection and cancer

From rodent to human: genetic dissection

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

Conict of interest statement

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

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2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

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2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

REVIEW: BRAIN CONTROL OF FOOD INTAKE

2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301327

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