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Neurobiology of Disease
journal homepage: www.elsevier.com/locate/ynbdi
Review
a r t i c l e
i n f o
Article history:
Received 14 January 2014
Revised 9 April 2014
Accepted 21 April 2014
Available online 26 April 2014
Keywords:
Leptin
Neurodegeneration
Obesity
Diabetes
Leptin resistance
Metabolic disorder
a b s t r a c t
As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied
by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop
tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have
shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal
models have provided insights into the complex relationships between these conditions. Experimentally, the
fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specically, leptin minimizes
neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and
energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to
the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative
diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons
from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin
resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and
treatment of neurodegenerative disease.
2014 Elsevier Inc. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . .
Alzheimer's disease and associated metabolic dysfunction .
Parkinson's disease and associated metabolic dysfunction .
Leptin action in the central nervous system (CNS) . . . . . . .
Leptin receptor isoforms and animal models of leptin inactivity .
Leptin and the blood brain barrier . . . . . . . . . . . . . .
Mechanisms of pro-survival and neuroprotective effects of leptin
Leptin action in animal models of neurodegenerative disease . .
Alzheimer's disease . . . . . . . . . . . . . . . . . .
Parkinson's disease . . . . . . . . . . . . . . . . . . .
Leptin, obesity and neurodegeneration . . . . . . . . . . . .
Clinical applications for leptin . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
Corresponding author at: Belfer Building, Room 709, Albert Einstein College of
Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Available online on ScienceDirect (www.sciencedirect.com).
http://dx.doi.org/10.1016/j.nbd.2014.04.012
0969-9961/ 2014 Elsevier Inc. All rights reserved.
As the general population progressively ages, the prevalence of obesity, metabolic disease, and neurodegenerative disease continues to rise.
Neurodegenerative diseases belong to a class of diseases that appears to
be associated with age and obesity. Specically, Parkinson's disease and
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consistent with reduced body fat (Evidente et al., 2001). The weight loss
associated with PD would then result in less stored adipose, and thus
lowered serum leptin levels. This scenario is an example of the association between low leptin levels in the brain and pathogenesis of neurodegenerative disease. Additional studies have provided evidence of an
association between type 2 diabetes and PD. Wang et al. discovered
that mouse models of T2DM exhibit increased accumulation of -synuclein stress and neuroinammation in the midbrain when challenged
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) a neurotoxin used to mimic cell death caused by PD suggesting that T2DM
mice are more likely to develop PD-associated dopaminergic cell
death than their non-diabetic counterparts (Wang et al., 2014).
Collectively, these ndings demonstrate the signicant, multidirectional interactions between metabolic disorders and neurodegenerative diseases.
Leptin action in the central nervous system (CNS)
Leptin action on the hypothalamus to provide a satiety signal was
the rst of the hormone's functions to be reported (Wurtman, 1996).
Since then, many additional functions of leptin have been dened that
are mediated through activating areas of the hypothalamus. These
other roles include anorectic signaling to the hypothalamus to regulate
energy balance (Myers et al., 2008), as well as partial regulation of reproductive function and bone metabolism (Ducy et al., 2000; Moschos
et al., 2002). More recently, the hypothalamus has been implicated in
mediating other central actions of leptin, specically in stimulation of
sympathetic nerve activity (Rahmouni and Morgan, 2007).
Other regions of the brain have been identied as areas that respond
to leptin (Leshan et al., 2006). In the hippocampus, leptin has been
shown to be important in modulating neuroplasticity (Harvey, 2007;
Oomura et al., 2006; Shanley et al., 2001), which has interesting implications for Alzheimer's disease (Carro, 2009). In the ventral tegmental
area, leptin, in conjunction with insulin, works with the brain's reward
system to reinforce eating behavior (Figlewicz et al., 2007). Widespread
leptin action has also been implicated in neural development, and
abnormal fetal or infant leptin levels are hypothesized to be risk factors
for development of metabolic disorders in adulthood (Louis and Myers,
2007; Udagawa and Otani, 2007).
Metabolic states such as obesity and starvation confer resistance to
the central actions of leptin, rendering the individual unresponsive to
the endogenous anorexic leptin signal, a biomarker of leptin action.
Ongoing research is investigating the various states of leptin resistance
and determining whether the central actions of leptin are globally or
selectively impaired in this resistant state (Enriori et al., 2011). Interestingly, it has been shown that the neuroprotective effects of leptin are
diminished in an environment of obesity (Johnston et al., 2011),
which has important clinical ramications for the expanding obesity
epidemic.
Leptin receptor isoforms and animal models of leptin inactivity
Six isoforms of the leptin receptor (Elmquist et al., 1998) have been
isolated in different areas of the brain, all performing different functions
(Bjorbak et al., 1998; Elmquist et al., 1998). The long form (Ob-Rb) is
predominantly responsible for activating multiple signal transduction
systems, while the short forms (Ob-Ra, Ob-Rc-f) of the leptin receptor
are responsible for bioavailability of leptin in the brain and mediation of
leptin crossing the bloodbrain barrier (BBB). It is critical to understand
the signal transduction pathways activated upon leptin binding to the
long form of its receptor, given that leptin provides an essential survival
signal to cells exposed to pro-apoptotic conditions. As summarized by
Zhang et al. (Zhang et al., 2007), after binding leptin, the leptin Ob-Rb
receptor forms a homodimer which results in autophosphorylation
and activation of Janus tyrosine kinase 2 (Jak2). Activated Jak2 can phosphorylate three sites of the intracellular domain of the leptin receptor,
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Fig. 1. Leptin signaling pathways and the mechanism and effects of leptin resistance. Multiple factors contribute to the accumulation of excess adipose tissue, including diet and nutrition,
genetic factors pertaining to metabolic activity and loci of fat deposition, and the process of aging. Adipocytes release the adipocytokine peptide hormone, leptin, into plasma circulation.
With normal circulating leptin levels, plasma leptin transport across the bloodbrain barrier (BBB) is facilitated by short-form leptin receptors in the cerebromicrovasculature. Leptin then
binds the long-form leptin receptor (Ob-Rb) to initiate intra-cellular leptin signaling. Binding the leptin receptor is essential to modulation of anti-apoptotic neuroprotective effects by
leptin. However, excess adipocyte deposition elevates circulating leptin, while unrestrained peripheral lipolysis and increased hepatic lipogenesis increase plasma triglyceride levels in
the obese state. It is theorized that in the hyperleptinemic state leptin resistance results from: 1) excess free triglyceride interference with transport of leptin across the BBB, and 2) blockade of distinct intracellular signaling pathways downstream of leptin. It is possible that leptin resistance results in attenuated leptin signaling, and attendant clinical pathology.
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leptin to stimulate these pathways lends a signicant survival advantage to cells exposed to leptin within a pro-apoptotic environment.
The Jak2 signaling pathway was among the rst to be shown experimentally to modulate the downstream pro-survival signal of leptin. In
cell cultures of mouse cortical cells, AG490, an inhibitor of Jak2, was
added to a solution of leptin and NMDA to assess for cell survival compared to cells exposed to only NMDA and leptin (Dicou et al., 2001).
Signicantly fewer cells survived in the group of cells exposed to
AG490. The group also investigated this phenomenon in vivo by injecting
a combination of ibotenate, leptin, and AG490 intracerebrally. When leptin was co-administered with ibotenate and the Jak2 inhibitor, all of the
neuroprotective effects of leptin were reversed. The Jak2 inhibitor
also fully reversed the anti-apoptotic role of leptin in hippocampal
neurons exposed to oxidative Fe 2+, glutamate, or an environment
lacking neurotrophic factors (Guo et al., 2008; Russo et al., 2004).
Furthermore, Jak2 inhibition reduced the leptin-induced rise in manganese superoxide dismutase (Mn-SOD) and B-cell lymphoma-extra
large (Bcl-XL) protein, both key elements in blocking apoptosis.
To further elucidate the anti-apoptotic mechanism of leptin, Russo,
et al. used a series of inhibitors of major signal transducers Jak2 inhibitor, PI3K inhibitor, p38MAPK inhibitor, and two different MEK inhibitors on neuroblastoma cells in vitro (Russo et al., 2004). After treating
all of the cells with leptin, they observed that serum-free neuroblastoma
cells were more vulnerable to apoptosis when in the presence of Jak2
inhibitor, PI3K inhibitor, or one of the two inhibitors of MEK, as measured by DNA fragmentation. However, the anti-apoptotic effects of
leptin were preserved after exposure to p38MAPK inhibitor or the
second MEK inhibitor. Decreased caspase-3 activity in the neuroblastoma
Fig. 2. Intra-cellular signaling pathways of leptin and their possible implications for Alzheimer's and Parkinson's diseases. Upon leptin binding and dimerization of the leptin
receptor (Ob-Rb), the intra-cellular, Ob-Rb-associated Jak2 tyrosine kinase is activated, which phosphorylates Ob-Rb tyrosine residues that recruit and activate several key transcription
factors and kinases, including signal transducer and activator of transcription (STAT) 3 and phosphoinositide-3-kinase (PI3K). In Alzheimer's disease conditions leptin modulates the
STAT3/AMPK pathway to inhibit the production of amyloid precursor protein (APP) secretase, mediating decreased production of beta-amyloid plaque. Meanwhile, the leptinmediated PI3K/AKT pathway inhibits downstream production of tau protein, which amasses to produce neurobrillary tangles (NFTs) in the pathologic Alzheimer's disease state. In
the context of Parkinson's disease, leptin modulates the phosphorylation of Ob-Rb tyrosine residues that activate mitogen-activated protein kinase (MAPK). MAPK then activates
cAMP response element-binding (CREB) protein, which has an anti-apoptotic effect on the cell. It is possible that leptin could mediate neuroprotective effects on dopaminergic cells
via the MAPK/CREB pathway in pathologic Parkinson's disease.
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cells upon inhibition of Jak2, MEK/ERK and PI3K pathways indicated the
importance of these pathways as mediators of leptin-induced neuroblastoma cell survival.
The role of the PI3K/Akt pathway in transduction of the leptinmediated survival signal was further conrmed in a study in which neuroblastoma cells were pretreated with 1-methyl-4-pyridinium (MPP+),
a neurotoxin that targets dopamine-producing neurons (Lu et al., 2006).
When the leptin-pretreated SH-SY5Y cells were exposed to both leptin
and PI3K inhibitor, it was found that PI3K inhibitor signicantly
inhibited leptin-associated neuroprotection against MPP+. Interestingly, this reversal of leptin-mediated neuroprotection was not observed
when cells were exposed to Jak2 inhibitor or MEK inhibitor. The
authors hypothesized that in neuroblastoma cells exposed to MPP+,
leptin-mediated neuroprotection involved a Jak2-independent pathway. Further studies on hippocampal cells conrmed that PI3K inhibitor
reduced the ability of leptin to protect these cells against glutamate
toxicity (Guo et al., 2008; Russo et al., 2004).
Following Russo's investigation into several of the major signaling
pathways implicated in leptin-induced neuroprotection, the importance of the MEK/ERK signaling pathway was conrmed when the pathway was found to activate and promote nuclear localization of cAMP
response element-binding protein (CREB), a known prosurvival transcription factor in dopaminergic cells (Weng et al., 2007). Inhibitors of
the MEK pathway were found to reverse the neuroprotective effects of
leptin administration by reduction of phosphorylation and activation
of ERK 1,2 and CREB, thus preventing the propagation of leptin signaling. Similarly, for neurons genetically modied by knocking out the
Jak2 gene or transfected with decoy DNA to prevent activation of
CREB, both neuron types lost the survival advantage of leptin upon
challenge with 6-OHDA.
Leptin action in animal models of neurodegenerative disease
Since the above evidence suggests that leptin confers a pro-survival
signal to neurons by interfering with the apoptotic cascade induced by
harsh environments, it is of considerable clinical relevance to examine
the role leptin plays in models of neurodegenerative disease. To what
extent can leptin salvage cells affected by the pathophysiological
processes of diseases such as Alzheimer's disease (AD) and Parkinson's
disease (PD)? If it can be shown to salvage these cells, what is the functional outcome of leptin treatment on such disease states?
Alzheimer's disease
Alzheimer's disease is characterized by pathologic buildup of two
neurotoxic substances: extracellular amyloid plaque, as a result of an
excess deposition of -amyloid (A); and intracellular neurobrillary
tangles (NFT), a consequence of hyperphosphorylation of tau protein
(Ittner and Gotz, 2011). Tau is a microtubule-associated protein localized largely in the axons of neuronal cells that promotes the binding
of microtubules and polymerization of tubulin to build crossbridges
between microtubules and to elongate the axon body (Harada et al.,
1994). Tau protein is regulated by various kinases, most notably by Protein Kinase N (PKN), which specically phosphorylates tau to promote
microtubule disarray responsible for NFT formation (Taniguchi et al.,
2001). In light of the common belief that the abnormal deposition of
both amyloid and NFT are central to the pathogenesis of AD, it has
been demonstrated that leptin plays a role in reversing both pathological hallmarks of AD and results in better neurological outcomes for the
disease state (Fewlass et al., 2004; Greco et al., 2009, 2010).
Modulation of tau protein phosphorylation by leptin represents a
signicant pathway for protection against Alzheimer's disease pathology.
Greco et al. found that, in cell cultures of Human neuroblastoma, SHSY5Y, leptin resulted in time- and concentration-dependent decreases
in phosphorylation at Ser396 of tau, which in turn affected the binding
of tau to microtubules in the cell. Further experimentation showed
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found that both amyloid plaques (size and number) as well as astrocyte
activation were decreased in calorie-restricted animals compared with
those with unlimited access to food. Clinical trials are currently underway to examine the inuence of caloric restriction on cognitive performance and slowing of cognitive decline in human patients above age 60
with mild cognitive impairment, with the hypothesis that caloric
restriction and lifestyle counseling would result in weight loss, reduction
of circulating leptin levels, decreased risk of dementia, and improvement
or reduction in the rate of decline in cognitive performance (Hospital
UoSPG, 2011). A meta-analysis performed on many studies of earlyphase Alzheimer's human patients supports the role of nutritional modication in prolonging life and expands on the role of caloric restriction in
animal models (Burgener et al., 2008).
An interest in using leptin to directly treat neurodegenerative disorders has been the focus of increasing attention. Matochik et al. demonstrated that 18 months of leptin replacement therapy at physiological
doses for patients with congenital leptin deciency resulted in signicant increases in gray matter volume in the anterior cingulated gyrus,
the inferior parietal lobule and the cerebellum but not in the hypothalamus and that this increased volume persisted over the next period of
18 months, reversing after an interval of withdrawal of leptin therapy
(Matochik et al., 2005; Paz-Filho et al., 2010). The clinical benet of leptin replacement therapy has important consequences for patients with
Alzheimer's disease, who have been found to have signicantly lowered
serum leptin levels (Power et al., 2001). Holden et al. prospectively
studied 2871 elderly subjects over a span of four years to nd that subjects with low serum leptin levels were more likely to develop AD than
patients with high leptin levels (Holden et al., 2009). Further studies
have demonstrated the correlation between low plasma levels of leptin
and early AD onset (Bigalke et al., 2011), while a study of 785 healthy
patients from the Framingham cohort over the course of 8.3 years revealed an association between elevated leptin levels and both increased
cerebral volume and decreased risk of dementia, noting a fourfold increase in risk of AD from the lowest to highest quartile of leptin levels
among the participants (Lieb et al., 2009). Of note, the neuroprotective
effects of high levels of leptin were observed among lean patients but
not among obese patients, likely because of leptin resistance among
the obese. Collectively, these ndings suggest exogenous leptin replacement therapy as a potential treatment method for leptin-decient
patients either before or after onset of neurodegenerative diseases
such as Alzheimer's and Parkinson's.
Another future potential therapeutic avenue for leptin involves the
use of viral vector-associated leptin gene therapy to deliver leptin to
specic receptor sites in the brain. Recently, Perez-Gonzalez et al.
found that leptin delivery via lentiviral vector into transgenic APP/PS1
mice, a rodent model that exhibits AD-like alterations due to overexpression of APP and PS1 proteins, reduced pathological A accumulation and improved synaptic density and neurite length in cortical
and hippocampal regions three months after vector delivery (PerezGonzalez et al., 2014). Elevation of endogenous brain expression of
leptin by leptin gene therapy has also been shown to restore euglycemia
in mouse models of type 1 diabetes (Ueno et al., 2006) and to improve
insulin sensitivity in type 2 diabetic models (Boghossian et al., 2006,
2007). While gene therapy with diverse viral vectors has been tested
frequently in clinical trials for its efcacy against both Alzheimer's and
Parkinson's diseases (Kaplitt et al., 2007; Marks et al., 2008, 2010), conclusive clinical trials of leptin application in gene therapy have yet to be
executed.
In spite of these promising ndings, it does not appear that any clinical trials are currently underway to directly test the impact of leptin
therapy on neurodegenerative disease by central or peripheral routes.
In the event that clinical trials of therapeutic leptin are undertaken,
they should take into account the obesity-induced leptin resistance at
both the cererobromicrovascular and signaling transduction level that
has been found to associate with neurodegenerative diseases such as
Alzheimer's disease (Bonda et al., 2014). Roth et al. in 2008 reported
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