You are on page 1of 9

Fat as an endocrine organ: influence of exercise

Jason R. Berggren, Matthew W. Hulver and Joseph A. Houmard


J Appl Physiol 99:757-764, 2005. doi:10.1152/japplphysiol.00134.2005

You might find this additional information useful...

This article cites 119 articles, 66 of which you can access free at:
http://jap.physiology.org/cgi/content/full/99/2/757#BIBL

This article has been cited by 1 other HighWire hosted article:


Sleep disruption is related to allelic variation in the ob gene
R. Lydic
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290 (4): R892-R893.
[Full Text] [PDF]

Medline items on this article's topics can be found at http://highwire.stanford.edu/lists/artbytopic.dtl


on the following topics:
Medicine .. Insulin
Oncology .. Insulin Resistance

Downloaded from jap.physiology.org on November 14, 2006


Oncology .. Insulin Sensitivity
Physiology .. Exertion
Medicine .. Diabetes
Medicine .. Exercise

Updated information and services including high-resolution figures, can be found at:
http://jap.physiology.org/cgi/content/full/99/2/757

Additional material and information about Journal of Applied Physiology can be found at:
http://www.the-aps.org/publications/jappl

This information is current as of November 14, 2006 .

Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially
those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American
Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society.
ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at http://www.the-aps.org/.
J Appl Physiol 99: 757–764, 2005;
doi:10.1152/japplphysiol.00134.2005. Invited Review

HIGHLIGHTED TOPIC Role of Exercise in Reducing the Risk of Diabetes


and Obesity

Fat as an endocrine organ: influence of exercise


Jason R. Berggren,1 Matthew W. Hulver,2 and Joseph A. Houmard1
1
Human Performance Laboratory and Department of Exercise and Sport Science,
East Carolina University, Greenville, North Carolina; and 2Pennington Biomedical
Research Center, Louisiana State University System, Baton Rouge, Louisiana

Berggren, Jason R., Matthew W. Hulver, and Joseph A. Houmard. Fat as an


endocrine organ: influence of exercise. J Appl Physiol 99: 757–764, 2005; doi:
10.1152/japplphysiol.00134.2005.—The prevalence of diabetes and obesity con-
tinues to increase. It is therefore important to identify the pathophysiology under-
lying these disorders. An inability of insulin to stimulate glucose uptake, i.e.,

Downloaded from jap.physiology.org on November 14, 2006


insulin resistance, appears to be a common link between diabetes and obesity. The
identification of various adipocyte-secreted cytokines (adipocytokines) that influ-
ence satiety, energy balance, and insulin sensitivity provide a novel target for the
treatment of these disorders. Adipocytokines are differentially expressed with
obesity and diabetes, making them a strong candidate for linking insulin resistance
to these pathological conditions. This review explores the role of adipocytokines in
insulin action and examines the effect of exercise training on adipocytokine
content.
adipocytokines; insulin sensitivity; metabolism

ALTHOUGH ONCE THOUGHT TO BE a mere storage depot of excess Exercise may improve insulin sensitivity by modulating the
energy, it is now apparent that adipose tissue is an endocrine plasma content and/or function of adipocytokines. Therefore,
organ and plays a prominent role in energy metabolism. The this review will focus on the following topics: 1) what are the
discovery of leptin, a satiety hormone secreted by adipose roles of adipocytokines in skeletal muscle substrate metabo-
tissue, led us to change the way we view the role of adipose lism and 2) what effect does exercise have on circulating levels
tissue in nutrient metabolism. In addition to leptin, other of adipocytokines?
cytokines including tumor necrosis factor (TNF)-␣, interleu-
kin-6 (IL-6), resistin, visfatin, acylation stimulation protein, ADIPOCYTOKINES, INSULIN RESISTANCE, DIABETES,
and adiponectin have been identified as adipose-secreted pro- AND OBESITY
teins that are collectively referred to as adipocytokines. Adi- Adiponectin. Adiponectin, also referred to as AdipoQ (47)
pocytokines have numerous functions that include regulation and Acrp 30, is a 30-kDa protein that is encoded by apM-1 (69)
of satiety, carbohydrate and lipid metabolism, and insulin and expressed and secreted only by adipose tissue. Adiponec-
sensitivity. They are differentially expressed with obesity and tin, which contains an NH4-terminal collagenous domain and
diabetes. Metabolic syndrome is characterized as a cluster of COOH-terminal globular domain, circulates as either low mo-
metabolic conditions including excess abdominal fat, hyper- lecular weight trimer-dimer (180 kDa) or high molecular
glycemia, hyperlipidemia, and hyperinsulinemia (75). Periph- weight complex (⬎400 kDa) (83, 84). Pajvani et al. (83, 84)
eral insulin resistance appears to be the common mediator of recently reported that the higher molecular weight complex is
altered nutrient metabolism observed in these disorders. Be- the more biologically active form of the protein. However,
cause adipocytokines have been shown to influence insulin most human clinical intervention studies measure total adi-
signaling, regulation of these cytokines may play a role in the ponectin, which is proportional to the higher molecular weight
etiology of insulin resistance, obesity, and diabetes by altering complex, via commercially available kits (103).
or influencing carbohydrate and/or lipid metabolism. The study Adiponectin increases skeletal muscle fatty acid oxidation
of these novel proteins is important as the prevalence of and reduces plasma glucose concentrations through activation
metabolic syndrome, diabetes, and obesity are increasing at of adenosine monophosphate-activated protein kinase (AMPK)
epidemic rates and represent a large portion of health care (Table 1) (113). Both the globular domain and full-length
costs. Weight reduction and exercise are common nonpharma- adiponectin activated AMPK in skeletal muscle (113). Activa-
ceutical interventions for the treatment of insulin resistance. tion of AMPK leads to phosphorylation, and thus inhibition, of
acetyl coenzyme A carboxylase. Acetyl coenzyme A carbox-
Address for reprint requests and other correspondence: J. R. Berggren, 363 ylase is the regulated step in malonyl-CoA production and
Ward Sports Medicine Bldg., East Carolina Univ., Greenville, NC 27858 subsequent fatty acid biosynthesis. Malonyl-CoA is also a
(E-mail: berggrenj@mail.ecu.edu). potent inhibitor of carnitine palmitoyl transferase-1, the rate-
http://www. jap.org 8750-7587/05 $8.00 Copyright © 2005 the American Physiological Society 757
Invited Review
758 FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE

Table 1. Role of adipocytokines on skeletal muscle substrate utilization in humans


Adipocytokine Mechanism of Action Function

Adiponectin AMPK activation (113) Increase substrate utilization (113)


Leptin AMPK activation (72, 73) Increase substrate utilization (72, 73)
TNF-␣ Serine phosphorylation of IRS-1* (43) Inhibit glucose uptake* (43)
Resistin unknown unknown
IL-6 unknown Stimulate FAO and lipolysis† (105)
Mechanism and function of the adipocytokines on human skeletal muscle carbohydrate and lipid metabolism. Reference numbers are given in parentheses.
*Results from animal models that have not been confirmed in humans. †In adipose tissue.

limiting enzyme of fatty acid uptake into the mitochondria. sumption (V̇O2 max)] (29) nor an acute bout (30 min) of higher
Therefore, a reduction in malonyl-CoA removes inhibition of intensity (79%) running altered plasma adiponectin concentra-
mitochondrial fatty acid uptake and stimulates fatty acid oxi- tion in healthy men and women (62). Six weeks of cycle
dation, as well as reduces lipid biosynthesis. Because lipid training (60 min/day, 5 days/wk), which increased insulin
accumulation is associated with peripheral insulin resistance, sensitivity, did not increase plasma adiponectin concentration
increased circulating adiponectin would be favorable. in healthy men. Moreover, a 3-wk exercise intervention in
Adiponectin mRNA expression in adipose tissue (47) and patients with Type 2 diabetes did not alter adiponectin despite
plasma protein content (4) are reduced with obesity and dia- improvements in insulin action (117). Finally, a body weight-

Downloaded from jap.physiology.org on November 14, 2006


betes. Additionally, diabetes, obesity, and metabolic syndrome controlled (no reduction in body mass or fat mass) 6-mo
susceptibility locus has been mapped to chromosome 3q27, exercise intervention (4 days/wk for ⬃45 min at 65– 80% peak
which encodes adiponectin (14, 106). Single nucleotide poly- O2 consumption) increased insulin sensitivity (98%) despite no
morphisms of the adiponectin gene have also been associated change in plasma adiponectin (50). Although weight loss is
with the onset of diabetes (119). The relationship between associated with increased adiponectin levels (115), chronic
plasma adiponectin and insulin action appears independent of exercise without reductions in body weight does not affect
body mass index (BMI) or body fat (56). When subjects are plasma adiponectin levels in insulin-resistant populations (50).
matched for BMI and stratified according to insulin sensitivity, Thus the exercise-mediated enhancement of insulin action
differences in plasma adiponectin were related to differences in appears to be independent of changes in plasma adiponectin
insulin action (56). Furthermore, insulin-resistant lean individ- (116). However, the level of weight loss may be an important
uals have reduced plasma content of adiponectin compared determinant of changes in plasma adiponectin levels. A 6-mo
with insulin-sensitive subjects (1). dietary intervention in conjunction with an exercise program
It has been reported that lean and obese African Americans that resulted in a 3% decrease in body fat (13% decrease in
(AAs) have reduced skeletal muscle fatty acid oxidation and total fat mass) did not have an effect on plasma adiponectin
increased lipid accumulation compared with lean Caucasians levels (92). However, other lifestyle modification programs
(88), which is consistent with decreased AMPK activation and that resulted in greater weight loss increased plasma adiponec-
decreased adiponectin. Interestingly, both lean and obese AAs tin and insulin sensitivity (23). The current evidence would
have reduced fasting plasma adiponectin levels compared with suggest that exercise-induced improvements in insulin action
their Caucasian counterparts (49). Thus reduced plasma adi- occur independently of changes in plasma adiponectin. Addi-
ponectin levels, specifically in obese and AA populations, may tionally, the observation that the effects of exercise and weight
contribute to a predisposition to weight gain and insulin resis- loss on insulin action are additive may indicate that each
tance. modality mediates its effects through distinct pathways(17).
Plasma adiponectin is positively associated with enhanced Leptin. In the early 1990s it was discovered that defects in
insulin signal transduction in skeletal muscle (99) and a re- the ob gene lead to obesity in the ob/ob mouse (120). Leptin is
duced risk of developing diabetes (97). Administration of a product of the ob gene and circulates as a 16-kDa protein
adiponectin reverses insulin resistance in mice and reduced (120). Expression and secretion of leptin occurs primarily in
intramuscular triglycerides (114) and adiponectin knockout white adipose tissue (13, 31, 33, 59); however, additional
mice have impaired insulin sensitivity. Moreover, plasma adi- physiological sites of production have been established such as
ponectin is increased by surgically induced (gastric bypass) the stomach (6), brain (22, 111), placenta (67), skeletal muscle
and diet-induced weight loss, both of which are associated with (109), bone (91), and arterial endothelium (85). Plasma leptin
improved insulin action (50).
Because exercise training has a profound effect on the Table 2. Effect of exercise and weight loss on circulating
prevention and treatment of obesity and diabetes, it is logical to adipocytokines in humans
hypothesize that these effects may be mediated through adi-
ponectin regulation. However, because exercise training is Adipocytokine Obesity Exercise Weight Loss
associated with weight loss, it is important to discern the
Adiponectin 2(4, 47) 7(29, 50, 62) 1(50, 115)
independent effects of exercise without the confounding influ- Leptin 1(71) 7 (11, 45)2(21) 2(11, 90)
ence of reductions in fat mass. TNF-␣ 1(42, 44, 57) 7 (19, 94) 12 (36, 76)
Plasma adiponectin has been measured in response to acute Resistin 7NA NA NA
exercise bouts as well as moderate to long-term training pro- IL-6 1(57) 1 (19, 82, 104, 168) 2 (76)
grams in a variety of populations (Table 2). Neither an acute 1, Upregulation; 2, downregulation; 7, nonresponsive; 12, conflicting
bout of stationary cycling [60 min at 65% maximal O2 con- results; NA, information not available.

J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org


Invited Review
FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE 759
exhibits a circadian rhythm with the highest concentrations primarily due to reduced fat mass and/or a result of the
occurring near midnight and lowest concentrations near mid- negative energy balance induced by the previous exercise bout.
morning (8, 31, 34, 52). The diurnal rhythm of leptin secretion TNF-␣. TNF-␣ is a proinflammatory cytokine secreted from
is hormonally (growth hormone, insulin, cortisol) influenced a variety of cells including macrophages, muscle (94), and
(2, 108), is dependent on gender (3, 93) and energy availability adipose tissue (44). Recent evidence indicates that most of the
(3, 16, 41, 108), and may be altered by meal timing (95) and TNF-␣ secreted by adipose tissue is derived from macrophage
composition (9, 38). infiltration or other nonfat cell sources (25–27). TNF-␣ is a
Similar to adiponectin, leptin directly, or indirectly through 26-kDa protein that undergoes posttranslational modification
hypothalamic-mediated responses, activates AMPK in skeletal to form its active 17-kDa structure (74). TNF-␣ signaling is
muscle, thus increasing fatty acid oxidation and glucose uptake mediated by the transmembrane receptors TNF-␣ receptor 1
(72, 73). Administration of recombinant leptin to the ob/ob (p55) and TNF-␣ receptor 2 (p75). Although extensively stud-
mouse resulted in reductions in food intake and weight loss ied in cachexia, autoimmune disease, rheumatoid arthritis,
(31, 34). Leptin has thus been implicated in the control of sepsis, and other inflammatory disorders, the role of TNF-␣
energy intake and expenditure as well as reproductive function and its association with obesity and diabetes is less understood.
(34). Hyperleptinemia is commonly observed with insulin Infusion of TNF-␣ in rats impaired insulin-stimulated whole
resistance and Type 2 diabetes mellitus (71), and circulating body glucose disposal (43). TNF-␣ mediates insulin resistance
leptin concentrations correlate with measures of adiposity, via serine phosphorylation of insulin receptor substrate (IRS-1)
such as BMI, body fat percent, and total fat mass in humans in skeletal muscle, which inhibits the ability of insulin to
and animals (71). stimulate GLUT-4 translocation to the cell membrane and

Downloaded from jap.physiology.org on November 14, 2006


Plasma leptin decreases acutely during fasting or energy therefore reduces glucose uptake (43). Conversely, inhibition
restriction and increases with refeeding and overfeeding. Thus of TNF-␣ results in increased insulin-stimulated IRS-1 tyrosine
it is logical that exercise, a modality that alters systemic energy phosphorylation (10, 43). The ability of TNF-␣ to serine
flux and balance, would change plasma leptin concentration. phosphorylate IRS-1 may be mediated via diacylglycerol
Many studies have examined the effects of exercise on circu- (DAG). Incubating intact rat skeletal muscle strips with TNF-␣
lating levels of leptin with the thought that leptin sensitivity significantly increased palmitate incorporation into DAG (7).
would be improved and plasma leptin concentrations reduced. This is important because DAGs are known activators of
Circulating leptin has been measured in response to short- (45) conventional and novel protein kinase C isoforms that serine
and long-term exercise training (11, 39, 51, 60, 80, 86, 87, 90, phosphorylate, and thus inhibit, IRS-1. Therefore, as indicated
101) and after single bouts of exercise (maximal, submaximal, by animal models, conditions associated with elevated TNF-␣
short duration, and long duration) (20, 21, 24, 30, 39, 53, 61, would be accompanied by insulin resistance.
63– 65, 77, 81, 87, 89, 96, 102, 110, 118). Short-term training Although not without conflicting results, it appears that
does not influence fasting plasma leptin levels (45). Long-term obesity is associated with elevated adipose tissue mRNA ex-
exercise training decreases circulating leptin, but generally not pression of TNF-␣, which is also positively associated with
independent of changes in fat mass (11, 60, 80, 87, 90, 101). hyperinsulinemia (42, 44, 57, 112). Paradoxically, inhibition of
Several long-term training investigations have demonstrated TNF-␣ in obese diabetic patients had no effect on insulin
reductions in plasma leptin independent of weight reduction sensitivity (79). Although coculture of human skeletal muscle
(40, 51, 86), but it is unclear whether these changes were due with adipocytes impaired insulin signaling, the effect was
to long-term exercise training or were a result of the last independent of TNF-␣ (18). Additionally, incubating human
exercise bout. Studies examining the leptin response to single skeletal muscle with TNF-␣ did not impair insulin-mediated
bouts of exercise have produced equivocal results, but it glucose uptake (78), and some reports indicate an actual
appears that circulating leptin levels are only decreased by increase in glucose uptake (12). Thus human skeletal muscle
exercise bouts of considerably high intensity (21) and long glucose disposal is not hindered by TNF-␣. Because only
duration (20, 61, 64, 65, 81, 118). limited information is available regarding TNF-␣ and human
In a report from Hilton and Loucks (41), energy intake and skeletal muscle carbohydrate and lipid metabolism, it is diffi-
exercise-associated energy expenditure were controlled to dis- cult to provide a rationale for the conflicting results observed
tinguish the independent effects of energy availability and with these studies and previously reported results from animal
exercise stress on the diurnal leptin rhythm in healthy young studies.
women. When dietary energy intake was sufficient to compen- Because TNF-␣ is an inflammatory cytokine produced by a
sate for the energy cost of exercise, the suppressive effects of variety of cells, distinguishing the effects of exercise on TNF-␣
exercise on 24-h leptin levels were prevented. Thus the only content is difficult. TNF-␣ receptor (p55 and p75) knockout
influence of exercise on the 24-h mean and amplitude of leptin mice have elevated TNF-␣ mRNA expression in soleus mus-
was due to an induction of a negative energy balance caused by cle, whereas no difference was observed in gastrocnemius
the energy cost of exercise. Furthermore, they concluded that muscle (54). In this model, acute exercise (1 h swimming)
the diurnal rhythm of leptin depends on energy and/or carbo- reduced skeletal muscle TNF-␣ mRNA expression to control
hydrate availability, which are variables directly influenced by values. In a human study examining diabetes patients and
exercise. weight-matched controls, an acute bout of exercise (25 min at
On the basis of the current evidence, reductions in circulat- 60% V̇O2 peak) had no effect on plasma TNF-␣ levels (94).
ing leptin in response to short-term exercise and/or single bouts Plasma concentration of TNF-␣ is unchanged after prolonged
of exercise do not appear to be due to exercise stress but are endurance exercise (6 h) in trained men (19). Conversely, a
more likely the result of an induction of a negative energy combination of aerobic (aqua exercise 60% V̇O2 peak for 60
balance. A change in leptin after long-term exercise training is min) and resistance training (1 set/wk, 1 set ⫽ 8 –12 repeti-
J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org
Invited Review
760 FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE

tions) for 10 wk tended to increase plasma TNF-␣ in female (57). When subjects were matched for BMI, plasma IL-6 was
participants, which was significantly related to a decrease in independently related to level of insulin resistance (57). Sys-
visceral fat mass (36). A 6-mo diet and physical activity (3/wk, temic release of IL-6 from subcutaneous adipose tissue was
30 min 60 – 80% V̇O2 peak) intervention resulted in a decrease in also positively correlated with BMI and percent body fat (57).
serum TNF-␣ in subjects with impaired glucose tolerance and Contradictory to this evidence linking elevated plasma IL-6 to
tended to decrease serum TNF-␣ in diabetic subjects (76). insulin resistance, recent investigations have failed to show a
However, because there was weight loss, it is difficult to relationship between IL-6 and insulin resistance (98). Infusion
determine the individual effect of exercise alone in these of IL-6 in humans did not impair muscle glucose uptake or
studies (29, 68). Thus TNF-␣, as with adiponectin, does not whole body glucose disposal, nor did it affect endogenous
appear to be influenced by exercise independent of weight loss. glucose production (98). Additionally, recent human in vivo
Resistin. The recent discovery of resistin, a hormone ex- studies demonstrate that IL-6 infusion stimulates lipolysis and
pressed and secreted by adipocytes, provided promise for fat oxidation (105). Weight loss, which decreases long-chain
determining the link between obesity and diabetes (100). Re- fatty acyl CoA, is associated with decreased IL-6 (76). Rec-
sistin gene expression is induced during adipocyte differenti- onciliation of these conflicting results is not currently possible
ation (89). Although the exact mechanism of resistin function considering the relatively small amount of information avail-
has yet to be identified, Steppan et al. (100) observed increased able on IL-6. It is apparent that more research is needed to
circulating resistin levels in diet-induced and genetic models of determine the role of IL-6 in insulin action and its contribution
obesity. Inhibition of resistin in these models restored insulin to obesity and diabetes. Elevated levels of IL-6 often observed
action, whereas administration of resistin inhibited insulin with obesity and diabetes may be associative and not a direct

Downloaded from jap.physiology.org on November 14, 2006


action in control animals. cause of insulin resistance.
Surprisingly, the evidence linking resistin to diabetes and It has been well documented that acute exercise increases
obesity in humans is less clear. Serum content of resistin is plasma levels of IL-6 (19, 82, 104); however, the influence of
unaffected by obesity and insulin resistance in humans (37). exercise on the release of IL-6 from adipose tissue has only
Lee et al. (66) compared BMI, fat mass, and insulin action to recently been investigated. After 1 h of cycling at 60% V̇O2 max,
resistin levels in 243 subjects (male and female) and observed subcutaneous abdominal adipose tissue increased IL-6 produc-
no relationship. There was also no difference in resistin be- tion starting at 30 min of recovery and continued for a least 3 h
tween lean and obese insulin-resistant subjects. Serum resistin postexercise (68). This temporal release of IL-6 precedes the
can be elevated in Type 2 diabetes patients, but there was no increase in fatty acid mobilization from adipose tissue stores
relationship between adiposity and insulin (70), whereas others after exercise. Combined with the observation that IL-6 infu-
have reported no difference in obese, obese diabetic, and sion stimulates lipolysis, this data provides rationale for the
nonobese subjects (37). Although there are conflicting reports hypothesis that IL-6 has a role in regulating lipid metabolism
as to the relationship of resistin to adiposity (5), most investi- after acute exercise. Additionally, 3 h of cycling at 60%
gations agree that resistin is not related to insulin resistance V̇O2 max increased IL-6 mRNA expression in subcutaneous
(107). adipose tissue and plasma content (55). This effect was blunted
To date, there is no information on the interaction between by carbohydrate ingestion (55), suggesting that nutrient avail-
exercise and resistin. Because the role of resistin in regulating ability may affect IL-6 production. However, more research is
insulin action is unclear at this time, there appears to be little needed to clarify the role of nutrient availability on IL-6
rationale to investigate the influence of exercise on this partic- production.
ular adipocytokine. At rest, skeletal muscle does not appear to contribute to
Interleukin (IL-6). IL-6 is a multifunctional cytokine se- fasting levels of plasma IL-6 (28). However, skeletal muscle
creted by numerous cell types including immune cells, skeletal contraction increases IL-6 mRNA expression and IL-6 protein
muscle, and adipose tissue. In an effort to determine function, release from muscle. An acute bout of cycling (25 min at 60%
Kim et al. (58) pretreated mice with IL-6 before a hyperinsu- V̇O2 peak) increased IL-6 release from skeletal muscle. In sup-
linemic-euglycemic clamp. IL-6 blunted skeletal muscle glu- port of the notion that nutrient availability effects IL-6 produc-
cose disposal as well as IRS-1-associated phosphatidylinositol tion, Steensberg et al. (98) determined that contraction-induced
3-kinase activity (58). Moreover, IL-6 treatment increased IL-6 release is highest when muscle glycogen content is low.
levels of intramuscular fatty acyl CoA (58). Intramuscular The current evidence does suggest that exercise alters circu-
long-chain fatty acyl CoAs are increased with obesity (48), are lating IL-6 concentrations, but more work is needed to discern
negatively related to insulin sensitivity (15), and decrease with the metabolic implications of these changes.
weight loss (46). The effect of IL-6 on insulin action and lipid
accumulation was similar to that of lipid infusion alone, indi- CONCLUSIONS
cating that IL-6 effects on muscle metabolism may be mediated
through increased lipid availability. Decreases in fatty acid Adipocytokines signal a variety of metabolic functions in-
oxidation and increased fatty acid uptake have been proposed cluding satiety, lipid mobilization, and utilization, and modu-
as possible mechanisms of increased lipid accumulation, which late insulin-mediated glucose disposal. Their secretion is mod-
causes insulin resistance, with obesity (48) and diabetes. Thus ulated by energy flux, i.e., carbohydrate and lipid availability
elevated fasting plasma IL-6 concentrations would be detri- (35). Obesity, which is a condition of excess adipose tissue, is
mental to insulin action. associated with insulin resistance and diabetes. A strong link
Serum IL-6 levels are elevated with obesity (57) and diabe- between these disorders is altered secretion of adipocytokines.
tes (28) and are negatively related with insulin-stimulated Of the various adipocytokines, decreased adiponectin appears
glucose disposal during a euglycemic-hyperinsulinemic clamp to show the strongest relationship with insulin resistance and
J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org
Invited Review
FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE 761
obesity in humans. Reduced adiponectin results in decreased GH deficiency: effects of GH replacement. J Clin Endocrinol Metab 86:
AMPK activation and subsequently decreased skeletal muscle 3499 –3506, 2001.
3. Ahren B. Diurnal variation in circulating leptin is dependent on gender,
fatty acid oxidation contributing to increased lipid accumula- food intake and circulating insulin in mice. Acta Physiol Scand 169:
tion and insulin resistance. Although exercise is a common 325–331, 2000.
modality for the management of insulin resistance, when body 4. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J,
weight is maintained there appears to be little effect on the Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H,
Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M,
secretion of adiponectin and leptin. Adiponectin and leptin act
Ohmoto Y, Funahashi T, and Matsuzawa Y. Paradoxical decrease of
via AMPK activation in skeletal muscle to increase fatty acid an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res
oxidation and glucose disposal. Considering that exercise Commun 257: 79 – 83, 1999.
(muscle contraction) stimulates the same pathway, modulating 5. Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shi-
adipocytokines levels may not be necessary for exercise in- mada A, and Saruta T. Correlation between serum resistin level and
adiposity in obese individuals. Obes Res 11: 997–1001, 2003.
duced improvements in insulin sensitivity. The effect of resis- 6. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bor-
tin and TNF-␣ on human insulin resistance appears minimal toluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-
and associations may be indirect. Acute exercise increases IL-6 Brustel Y, and Lewin MJ. The stomach is a source of leptin. Nature
secretion from adipose tissue, which increases fatty acid avail- 394: 790 –793, 1998.
ability. Despite the evidence linking increased fatty acid avail- 7. Bruce CR and Dyck DJ. Cytokine regulation of skeletal muscle fatty
acid metabolism: effect of interleukin-6 and tumor necrosis factor-␣.
ability to insulin resistance, exercise-trained muscle may be Am J Physiol Endocrinol Metab 287: E616 –E621, 2004.
protected from fat-induced insulin resistance. It should be 8. Casanueva FF and Dieguez C. Neuroendocrine regulation and actions
noted that the addition of an exercise regimen to a weight loss of leptin. Front Neuroendocrinol 20: 317–363, 1999.

Downloaded from jap.physiology.org on November 14, 2006


program results in an additive effect on insulin action that may 9. Cha MC, Chou CJ, and Boozer CN. High-fat diet feeding reduces the
be mediated by the more consistent effect of fat mass loss on diurnal variation of plasma leptin concentration in rats. Metabolism 49:
503–507, 2000.
adipocytokine regulation. In conclusion, it appears that exer- 10. Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, and Bryer-Ash M.
cise may not directly influence adipocytokine regulation. An in vivo model for elucidation of the mechanism of tumor necrosis
Weight loss, however, does appear to regulate adipocytokines factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differ-
in a manner that may enhance insulin action. These observa- ential regulation of insulin signaling by TNF-alpha. Endocrinology 139:
4928 – 4935, 1998.
tions imply that these two common interventions for obesity 11. Christensen JO, Svendsen OL, Hassager C, and Christiansen C.
and insulin resistance function through divergent cellular path- Leptin in overweight postmenopausal women: no relationship with met-
ways. abolic syndrome X or effect of exercise in addition to diet. Int J Obes
Relat Metab Disord 22: 195–199, 1998.
FUTURE RESEARCH DIRECTIONS 12. Ciaraldi TP, Carter L, Mudaliar S, Kern PA, and Henry RR. Effects
of tumor necrosis factor-alpha on glucose metabolism in cultured human
Although recent investigations have studied the role of muscle cells from nondiabetic and Type 2 diabetic subjects. Endocrinol-
ogy 139: 4793– 4800, 1998.
adipocytokines in obesity, diabetes, and insulin resistance, 13. Cinti S, Frederich RC, Zingaretti MC, De Matteis R, Flier JS, and
more research is needed on the tissue-specific secretion and Lowell BB. Immunohistochemical localization of leptin and uncoupling
response of these cytokines. For example, a recent study from protein in white and brown adipose tissue. Endocrinology 138: 797– 804,
Gallagher et al. (32) demonstrated that with obesity there is not 1997.
only an increase in intramuscular fat storage but also an 14. Comuzzie AG, Funahashi T, Sonnenberg G, Martin LJ, Jacob HJ,
Black AE, Maas D, Takahashi M, Kihara S, Tanaka S, Matsuzawa
increase in fat deposition between muscle fibers. Interestingly, Y, Blangero J, Cohen D, and Kissebah A. The genetic basis of plasma
the amount of deposition is different depending on ethnicity. In variation in adiponectin, a global endophenotype for obesity and the
light of these findings, future work will need to characterize metabolic syndrome. J Clin Endocrinol Metab 86: 4321– 4325, 2001.
these lipid pools with regard to adipocytokine secretion relative 15. Cooney GJ, Thompson AL, Furler SM, Ye J, and Kraegen EW.
Muscle long-chain acyl CoA esters and insulin resistance. Ann NY Acad
to other lipid pools (i.e., subcutaneous and visceral) because
Sci 967: 196 –207, 2002.
these intermuscular lipid pools may serve as a very important 16. Dallongeville J, Hecquet B, Lebel P, Edme JL, Le Fur C, Fruchart
local modulator of skeletal muscle metabolism. Moreover, are JC, Auwerx J, and Romon M. Short term response of circulating leptin
these pools more affected by exercise than other lipid pools? to feeding and fasting in man: influence of circadian cycle. Int J Obes
Only when we can fully elucidate the cross-talk mechanisms Relat Metab Disord 22: 728 –733, 1998.
17. Dengel DR, Pratley RE, Hagberg JM, Rogus EM, and Goldberg AP.
between various tissues including muscle, adipose tissue, and Distinct effects of aerobic exercise training and weight loss on glucose
the liver will we fully understand the complex nature of insulin homeostasis in obese sedentary men. J Appl Physiol 81: 318 –325, 1996.
resistance. Future research should discern the mechanisms by 18. Dietze D, Koenen M, Rohrig K, Horikoshi H, Hauner H, and Eckel
which increased physical activity promotes insulin sensitivity J. Impairment of insulin signaling in human skeletal muscle cells by
and its relation to adipocytokines. Although the concentrations co-culture with human adipocytes. Diabetes 51: 2369 –2376, 2002.
19. Drenth JP, Van Uum SH, Van Deuren M, Pesman GJ, Van der
of adipocytokines are only marginally influenced by exercise, Ven-Jongekrijg J, and Van der Meer JW. Endurance run increases
it is possible that the signaling effects of these cytokines are circulating IL-6 and IL-1ra but downregulates ex vivo TNF-␣ and IL-1␤
modulated after training. production. J Appl Physiol 79: 1497–1503, 1995.
20. Duclos M, Corcuff JB, Ruffie A, Roger P, and Manier G. Rapid leptin
decrease in immediate post-exercise recovery. Clin Endocrinol (Oxf) 50:
REFERENCES
337–342, 1999.
1. Abbasi F, Chu JW, Lamendola C, McLaughlin T, Hayden J, Reaven 21. Elias AN, Pandian MR, Wang L, Suarez E, James N, and Wilson AF.
GM, and Reaven PD. Discrimination between obesity and insulin Leptin and IGF-I levels in unconditioned male volunteers after short-term
resistance in the relationship with adiponectin. Diabetes 53: 585–590, exercise. Psychoneuroendocrinology 25: 453– 461, 2000.
2004. 22. Esler M, Vaz M, Collier G, Nestel P, Jennings G, Kaye D, Seals D,
2. Ahmad AM, Guzder R, Wallace AM, Thomas J, Fraser WD, and and Lambert G. Leptin in human plasma is derived in part from the
Vora JP. Circadian and ultradian rhythm and leptin pulsatility in adult brain, and cleared by the kidneys. Lancet 351: 879, 1998.

J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org


Invited Review
762 FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE

23. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella 44. Hotamisligil GS, Shargill NS, and Spiegelman BM. Adipose expres-
R, and Giugliano D. Effect of weight loss and lifestyle changes on sion of tumor necrosis factor-alpha: direct role in obesity-linked insulin
vascular inflammatory markers in obese women: a randomized trial. resistance. Science 259: 87–91, 1993.
JAMA 289: 1799 –1804, 2003. 45. Houmard JA, Cox JH, MacLean PS, and Barakat HA. Effect of
24. Essig DA, Alderson NL, Ferguson MA, Bartoli WP, and Durstine JL. short-term exercise training on leptin and insulin action. Metabolism 49:
Delayed effects of exercise on the plasma leptin concentration. Metab- 858 – 861, 2000.
olism 49: 395–399, 2000. 46. Houmard JA, Tanner CJ, Yu C, Cunningham PG, Pories WJ,
25. Fain JN, Bahouth SW, and Madan AK. TNFalpha release by the MacDonald KG, and Shulman GI. Effect of weight loss on insulin
nonfat cells of human adipose tissue. Int J Obes Relat Metab Disord 28: sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly
616 – 622, 2004. obese subjects. Diabetes 51: 2959 –2963, 2002.
26. Fain JN, Cheema PS, Bahouth SW, and Lloyd Hiler M. Resistin 47. Hu E, Liang P, and Spiegelman BM. AdipoQ is a novel adipose-
release by human adipose tissue explants in primary culture. Biochem specific gene dysregulated in obesity. J Biol Chem 271: 10697–10703,
Biophys Res Commun 300: 674 – 678, 2003. 1996.
27. Fain JN, Madan AK, Hiler ML, Cheema P, and Bahouth SW. 48. Hulver MW, Berggren JR, Cortright RN, Dudek RW, Thompson
Comparison of the release of adipokines by adipose tissue, adipose tissue RP, Pories WJ, MacDonald KG, Cline GW, Shulman GI, Dohm GL,
matrix, and adipocytes from visceral and subcutaneous abdominal adi- and Houmard JA. Skeletal muscle lipid metabolism with obesity. Am J
pose tissues of obese humans. Endocrinology 145: 2273–2282, 2004. Physiol Endocrinol Metab 284: E741–E747, 2003.
28. Febbraio MA, Steensberg A, Starkie RL, McConell GK, and King- 49. Hulver MW, Saleh O, MacDonald KG, Pories WJ, and Barakat HA.
well BA. Skeletal muscle interleukin-6 and tumor necrosis factor-alpha Ethnic differences in adiponectin levels. Metabolism 53: 1–3, 2004.
release in healthy subjects and patients with Type 2 diabetes at rest and 50. Hulver MW, Zheng D, Tanner CJ, Houmard JA, Kraus WE, Slentz
during exercise. Metabolism 52: 939 –944, 2003. CA, Sinha MK, Pories WJ, MacDonald KG, and Dohm GL. Adi-
29. Ferguson MA, White LJ, McCoy S, Kim HW, Petty T, and Wilsey J. ponectin is not altered with exercise training despite enhanced insulin
action. Am J Physiol Endocrinol Metab 283: E861–E865, 2002.

Downloaded from jap.physiology.org on November 14, 2006


Plasma adiponectin response to acute exercise in healthy subjects. Eur
J Appl Physiol 91: 324 –329, 2004. 51. Ishii T, Yamakita T, Yamagami K, Yamamoto T, Miyamoto M,
30. Fisher JS, Van Pelt RE, Zinder O, Landt M, and Kohrt WM. Acute Kawasaki K, Hosoi M, Yoshioka K, Sato T, Tanaka S, and Fujii S.
exercise effect on postabsorptive serum leptin. J Appl Physiol 91: Effect of exercise training on serum leptin levels in Type 2 diabetic
680 – 686, 2001. patients. Metabolism 50: 1136 –1140, 2001.
31. Friedman JM and Halaas JL. Leptin and the regulation of body weight 52. Kanabrocki EL, Hermida RC, Wright M, Young RM, Bremner FW,
in mammals. Nature 395: 763–770, 1998. Third JL, Ryan MD, Ayala DE, Johnson M, Nemchausky BA,
32. Gallagher D, Kuznia P, Heshka S, Albu J, Heymsfield SB, Goodpas- Shirazi P, Scheving LE, and Olwin JH. Circadian variation of serum
ter B, Visser M, and Harris TB. Adipose tissue in muscle: a novel leptin in healthy and diabetic men. Chronobiol Int 18: 273–283, 2001.
depot similar in size to visceral adipose tissue. Am J Clin Nutr 81: 53. Kanaley JA, Fenicchia LM, Miller CS, Ploutz-Synder LL, Weinstock
903–910, 2005. RS, Carhart R, and Azevedo JL Jr. Resting leptin responses to acute
and chronic resistance training in Type 2 diabetic men and women. Int J
33. Gong DW, Bi S, Pratley RE, and Weintraub BD. Genomic structure
Obes Relat Metab Disord 25: 1474 –1480, 2001.
and promoter analysis of the human obese gene. J Biol Chem 271:
54. Keller C, Keller P, Giralt M, Hidalgo J, and Pedersen BK. Exercise
3971–3974, 1996.
normalises overexpression of TNF-alpha in knockout mice. Biochem
34. Havel PJ. Role of adipose tissue in body-weight regulation: mechanisms
Biophys Res Commun 321: 179 –182, 2004.
regulating leptin production and energy balance. Proc Nutr Soc 59:
55. Keller C, Keller P, Marshal S, and Pedersen BK. IL-6 gene expression
359 –371, 2000.
in human adipose tissue in response to exercise — effect of carbohydrate
35. Havel PJ. Update on adipocyte hormones: regulation of energy balance
ingestion. J Physiol 550: 927–931, 2003.
and carbohydrate/lipid metabolism. Diabetes 53, Suppl 1: S143–S151,
56. Kern PA, Di Gregorio GB, Lu T, Rassouli N, and Ranganathan G.
2004. Adiponectin expression from human adipose tissue: relation to obesity,
36. Hayase H, Nomura S, Abe T, and Izawa T. Relation between fat insulin resistance, and tumor necrosis factor-␣ expression. Diabetes 52:
distributions and several plasma adipocytokines after exercise training in 1779 –1785, 2003.
premenopausal and postmenopausal women. J Physiol Anthropol Appl 57. Kern PA, Ranganathan S, Li C, Wood L, and Ranganathan G.
Human Sci 21: 105–113, 2002. Adipose tissue tumor necrosis factor and interleukin-6 expression in
37. Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin human obesity and insulin resistance. Am J Physiol Endocrinol Metab
E, and Smith SR. Relationship between serum resistin concentrations 280: E745–E751, 2001.
and insulin resistance in nonobese, obese, and obese diabetic subjects. 58. Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL,
J Clin Endocrinol Metab 89: 1844 –1848, 2004. Cho YR, Cline G, Kim YB, and Kim JK. Differential effects of
38. Herrmann TS, Bean ML, Black TM, Wang P, and Coleman RA. interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
High glycemic index carbohydrate diet alters the diurnal rhythm of leptin Diabetes 53: 1060 –1067, 2004.
but not insulin concentrations. Exp Biol Med (Maywood) 226: 1037– 59. Klein S, Coppack SW, Mohamed-Ali V, and Landt M. Adipose tissue
1044, 2001. leptin production and plasma leptin kinetics in humans. Diabetes 45:
39. Hickey MS, Considine RV, Israel RG, Mahar TL, McCammon MR, 984 –987, 1996.
Tyndall GL, Houmard JA, and Caro JF. Leptin is related to body fat 60. Kohrt WM, Landt M, and Birge SJ Jr. Serum leptin levels are reduced
content in male distance runners. Am J Physiol Endocrinol Metab 271: in response to exercise training, but not hormone replacement therapy, in
E938 –E940, 1996. older women. J Clin Endocrinol Metab 81: 3980 –3985, 1996.
40. Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, 61. Koistinen HA, Tuominen JA, Ebeling P, Heiman ML, Stephens TW,
Gavigan KE, Weidner ML, McCammon MR, Israel RG, and Caro and Koivisto VA. The effect of exercise on leptin concentration in
JF. Gender-dependent effects of exercise training on serum leptin levels healthy men and in Type 1 diabetic patients. Med Sci Sports Exerc 30:
in humans. Am J Physiol Endocrinol Metab 272: E562–E566, 1997. 805– 810, 1998.
41. Hilton LK and Loucks AB. Low energy availability, not exercise stress, 62. Kraemer RR, Aboudehen KS, Carruth AK, Durand RT, Acevedo
suppresses the diurnal rhythm of leptin in healthy young women. Am J EO, Hebert EP, Johnson LG, and Castracane VD. Adiponectin
Physiol Endocrinol Metab 278: E43–E49, 2000. responses to continuous and progressively intense intermittent exercise.
42. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, and Spiegelman Med Sci Sports Exerc 35: 1320 –1325, 2003.
BM. Increased adipose tissue expression of tumor necrosis factor-alpha 63. Kraemer RR, Johnson LG, Haltom R, Kraemer GR, Hebert EP,
in human obesity and insulin resistance. J Clin Invest 95: 2409 –2415, Gimpel T, and Castracane VD. Serum leptin concentrations in response
1995. to acute exercise in postmenopausal women with and without hormone
43. Hotamisligil GS, Budavari A, Murray D, and Spiegelman BM. replacement therapy. Proc Soc Exp Biol Med 221: 171–177, 1999.
Reduced tyrosine kinase activity of the insulin receptor in obesity- 64. Landt M, Lawson GM, Helgeson JM, Davila-Roman VG, Ladenson
diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 94: JH, Jaffe AS, and Hickner RC. Prolonged exercise decreases serum
1543–1549, 1994. leptin concentrations. Metabolism 46: 1109 –1112, 1997.

J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org


Invited Review
FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE 763
65. Leal-Cerro A, Garcia-Luna PP, Astorga R, Parejo J, Peino R, lidinedione-mediated improvement in insulin sensitivity. J Biol Chem
Dieguez C, and Casanueva FF. Serum leptin levels in male marathon 279: 12152–12162, 2004.
athletes before and after the marathon run. J Clin Endocrinol Metab 83: 85. Parhami F, Tintut Y, Ballard A, Fogelman AM, and Demer LL.
2376 –2379, 1998. Leptin enhances the calcification of vascular cells: artery wall as a target
66. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip of leptin. Circ Res 88: 954 –960, 2001.
R, Orlova C, and Mantzoros CS. Circulating resistin levels are not 86. Pasman WJ, Westerterp-Plantenga MS, and Saris WH. The effect of
associated with obesity or insulin resistance in humans and are not exercise training on leptin levels in obese males. Am J Physiol Endocri-
regulated by fasting or leptin administration: cross-sectional and inter- nol Metab 274: E280 –E286, 1998.
ventional studies in normal, insulin-resistant, and diabetic subjects. J Clin 87. Perusse L, Collier G, Gagnon J, Leon AS, Rao DC, Skinner JS,
Endocrinol Metab 88: 4848 – 4856, 2003. Wilmore JH, Nadeau A, Zimmet PZ, and Bouchard C. Acute and
67. Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J, and chronic effects of exercise on leptin levels in humans. J Appl Physiol 83:
Hauguel-de Mouzon S. Overexpression of placental leptin in diabetic 5–10, 1997.
pregnancy: a critical role for insulin. Diabetes 47: 847– 850, 1998. 88. Privette JD, Hickner RC, Macdonald KG, Pories WJ, and Barakat
68. Lyngso D, Simonsen L, and Bulow J. Interleukin-6 production in HA. Fatty acid oxidation by skeletal muscle homogenates from morbidly
human subcutaneous abdominal adipose tissue: the effect of exercise. obese black and white American women. Metabolism 52: 735–738, 2003.
J Physiol 543: 373–378, 2002. 89. Racette SB, Coppack SW, Landt M, and Klein S. Leptin production
69. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, and during moderate-intensity aerobic exercise. J Clin Endocrinol Metab 82:
Matsubara K. cDNA cloning and expression of a novel adipose specific 2275–2277, 1997.
collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). 90. Reseland JE, Anderssen SA, Solvoll K, Hjermann I, Urdal P, Holme
Biochem Biophys Res Commun 221: 286 –289, 1996. I, and Drevon CA. Effect of long-term changes in diet and exercise on
70. McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, plasma leptin concentrations. Am J Clin Nutr 73: 240 –245, 2001.
McTernan CL, Clark PMS, Smith SA, Barnett AH, and Kumar S. 91. Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O,
Resistin and Type 2 diabetes: regulation of resistin expression by insulin Gordeladze JO, and Drevon CA. Leptin is expressed in and secreted

Downloaded from jap.physiology.org on November 14, 2006


and rosiglitazone and the effects of recombinant resistin on lipid and from primary cultures of human osteoblasts and promotes bone miner-
glucose metabolism in human differentiated adipocytes. J Clin Endocri- alization. J Bone Miner Res 16: 1426 –1433, 2001.
nol Metab 88: 6098 – 6106, 2003. 92. Ryan AS, Nicklas BJ, Berman DM, and Elahi D. Adiponectin levels
71. Mendoza-Nunez VM, Garcia-Sanchez A, Sanchez-Rodriguez M, do not change with moderate dietary induced weight loss and exercise in
Galvan-Duarte RE, and Fonseca-Yerena ME. Overweight, waist cir- obese postmenopausal women. Int J Obes Relat Metab Disord 27:
cumference, age, gender, and insulin resistance as risk factors for hyper- 1066 –1071, 2003.
leptinemia. Obes Res 10: 253–259, 2002. 93. Saad MF, Riad-Gabriel MG, Khan A, Sharma A, Michael R, Jina-
72. Minokoshi Y and Kahn BB. Role of AMP-activated protein kinase in gouda SD, Boyadjian R, and Steil GM. Diurnal and ultradian rhyth-
leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans 31: micity of plasma leptin: effects of gender and adiposity. J Clin Endocri-
196 –201, 2003. nol Metab 83: 453– 459, 1998.
73. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, 94. Saghizadeh M, Ong JM, Garvey WT, Henry RR, and Kern PA. The
and Kahn BB. Leptin stimulates fatty-acid oxidation by activating expression of TNF alpha by human muscle. Relationship to insulin
AMP-activated protein kinase. Nature 415: 339 –343, 2002. resistance. J Clin Invest 97: 1111–1116, 1996.
74. Moller DE. Potential role of TNF-␣ in the pathogenesis of insulin 95. Schoeller DA, Cella LK, Sinha MK, and Caro JF. Entrainment of the
resistance and Type 2 diabetes. Trends Endocrinol Metab 11: 212–217, diurnal rhythm of plasma leptin to meal timing. J Clin Invest 100:
2000. 1882–1887, 1997.
75. Moller DE and Kaufman KD. Metabolic syndrome: a clinical and 96. Sliwowski Z, Lorens K, Konturek SJ, Bielanski W, and Zoladz JA.
molecular perspective. Annu Rev Med, 2004. Leptin, gastrointestinal and stress hormones in response to exercise in
76. Monzillo LU, Hamdy O, Horton ES, Ledbury S, Mullooly C, Jarema fasted or fed subjects and before or after blood donation. J Physiol
C, Porter S, Ovalle K, Moussa A, and Mantzoros CS. Effect of Pharmacol 52: 53–70, 2001.
lifestyle modification on adipokine levels in obese subjects with insulin 97. Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing
resistance. Obes Res 11: 1048 –1054, 2003. H, and Pfeiffer AF. Adiponectin and protection against Type 2 diabetes
77. Nindl BC, Kraemer WJ, Arciero PJ, Samatallee N, Leone CD, Mayo mellitus. Lancet 361: 226 –228, 2003.
MF, and Hafeman DL. Leptin concentrations experience a delayed 98. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjer-
reduction after resistance exercise in men. Med Sci Sports Exerc 34: ling P, van Hall G, Febbraio MA, and Pedersen BK. Acute interleu-
608 – 613, 2002. kin-6 administration does not impair muscle glucose uptake or whole-
78. Nolte LA, Hansen PA, Chen MM, Schluter JM, Gulve EA, and body glucose disposal in healthy humans. J Physiol 548: 631– 638, 2003.
Holloszy JO. Short-term exposure to tumor necrosis factor-alpha does 99. Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lind-
not affect insulin-stimulated glucose uptake in skeletal muscle. Diabetes say RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, and
47: 721–726, 1998. Tataranni PA. Plasma adiponectin concentration is associated with
79. Ofei F, Hurel S, Newkirk J, Sopwith M, and Taylor R. Effects of an skeletal muscle insulin receptor tyrosine phosphorylation, and low
engineered human anti-TNF-alpha antibody (CDP571) on insulin sensi- plasma concentration precedes a decrease in whole-body insulin sensi-
tivity and glycemic control in patients with NIDDM. Diabetes 45: tivity in humans. Diabetes 51: 1884 –1888, 2002.
881– 885, 1996. 100. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright
80. Okazaki T, Himeno E, Nanri H, Ogata H, and Ikeda M. Effects of CM, Patel HR, Ahima RS, and Lazar MA. The hormone resistin links
mild aerobic exercise and a mild hypocaloric diet on plasma leptin in obesity to diabetes. Nature 409: 307–312, 2001.
sedentary women. Clin Exp Pharmacol Physiol 26: 415– 420, 1999. 101. Thong FS, Hudson R, Ross R, Janssen I, and Graham TE. Plasma leptin
81. Olive JL and Miller GD. Differential effects of maximal- and moderate- in moderately obese men: independent effects of weight loss and aerobic
intensity runs on plasma leptin in healthy trained subjects. Nutrition 17: exercise. Am J Physiol Endocrinol Metab 279: E307–E313, 2000.
365–369, 2001. 102. Torjman MC, Zafeiridis A, Paolone AM, Wilkerson C, and Consid-
82. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, and ine RV. Serum leptin during recovery following maximal incremental
Pedersen BK. A trauma-like elevation of plasma cytokines in humans in and prolonged exercise. Int J Sports Med 20: 444 – 450, 1999.
response to treadmill running. J Physiol 513: 889 – 894, 1998. 103. Trujillo ME and Scherer PE. Adiponectin—journey from an adipocyte
83. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, secretory protein to biomarker of the metabolic syndrome. J Intern Med
Engel J, Brownlee M, and Scherer PE. Structure-function studies of 257: 167–175, 2005.
the adipocyte-secreted hormone Acrp30/adiponectin. Implications for 104. Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer-Kristensen J,
metabolic regulation and bioactivity. J Biol Chem 278: 9073–9085, 2003. and Pedersen BK. Bicycle exercise enhances plasma IL-6 but does not
84. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger change IL-1␣, IL-1␤, IL-6, or TNF-␣ pre-mRNA in BMNC. J Appl
JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Physiol 77: 93–97, 1994.
Kahn SE, Olefsky JM, Buchanan TA, and Scherer PE. Complex 105. Van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjer-
distribution, not absolute amount of adiponectin, correlates with thiazo- ling P, Hiscock N, Moller K, Saltin B, Febbraio MA, and Pedersen

J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org


Invited Review
764 FAT AS AN ENDOCRINE ORGAN: INFLUENCE OF EXERCISE

BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, and
Endocrinol Metab 88: 3005–3010, 2003. Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid
106. Vionnet N, Hani El H, Dupont S, Gallina S, Francke S, Dotte S, De oxidation by activating AMP-activated protein kinase. Nat Med 8:
Matos F, Durand E, Lepretre F, Lecoeur C, Gallina P, Zekiri L, Dina 1288 –1295, 2002.
C, and Froguel P. Genomewide search for Type 2 diabetes-susceptibil- 114. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K,
ity genes in French whites: evidence for a novel susceptibility locus for Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O,
early-onset diabetes on chromosome 3q27-qter and independent replica- Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H,
tion of a Type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita
Genet 67: 1470 –1480, 2000. M, Froguel P, and Kadowaki T. The fat-derived hormone adiponectin
107. Vozarova de Courten B, Degawa-Yamauchi M, Considine RV, and reverses insulin resistance associated with both lipoatrophy and obesity.
Tataranni PA. High serum resistin is associated with an increase in Nat Med 7: 941–946, 2001.
adiposity but not a worsening of insulin resistance in Pima Indians. 115. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL,
Diabetes 53: 1279 –1284, 2004. Chen CL, Tai TY, and Chuang LM. Weight reduction increases
108. Wagner R, Oberste-Berghaus C, Herpertz S, Blum WF, Pelz B, plasma levels of an adipose-derived anti-inflammatory protein, adiponec-
Hebebrand J, Senf W, Mann K, and Albers N. Time relationship tin. J Clin Endocrinol Metab 86: 3815–3819, 2001.
between circadian variation of serum levels of leptin, insulin and cortisol 116. Yatagai T, Nishida Y, Nagasaka S, Nakamura T, Tokuyama K,
in healthy subjects. Horm Res 54: 174 –180, 2000. Shindo M, Tanaka H, and Ishibashi S. Relationship between exercise
109. Wang J, Liu R, Hawkins M, Barzilai N, and Rossetti L. A nutrient- training-induced increase in insulin sensitivity and adiponectinemia in
sensing pathway regulates leptin gene expression in muscle and fat. healthy men. Endocr J 50: 233–238, 2003.
Nature 393: 684 – 688, 1998. 117. Yokoyama H, Emoto M, Araki T, Fujiwara S, Motoyama K, Mo-
110. Weltman A, Pritzlaff CJ, Wideman L, Considine RV, Fryburg DA, rioka T, Koyama H, Shoji T, Okuno Y, and Nishizawa Y. Effect of
Gutgesell ME, Hartman ML, and Veldhuis JD. Intensity of acute aerobic exercise on plasma adiponectin levels and insulin resistance in
exercise does not affect serum leptin concentrations in young men. Med Type 2 diabetes. Diabetes Care 27: 1756 –1758, 2004.

Downloaded from jap.physiology.org on November 14, 2006


Sci Sports Exerc 32: 1556 –1561, 2000. 118. Zaccaria M, Ermolao A, Roi GS, Englaro P, Tegon G, and Varnier
111. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert M. Leptin reduction after endurance races differing in duration and
G, Wilkinson D, and Esler M. Leptin is released from the human brain: energy expenditure. Eur J Appl Physiol 87: 108 –111, 2002.
influence of adiposity and gender. J Clin Endocrinol Metab 84: 2270 – 119. Zacharova J, Chiasson JL, and Laakso M. The common polymor-
2274, 1999. phisms (single nucleotide polymorphism [SNP] ⫹45 and SNP ⫹276) of
112. Xu H, Uysal KT, Becherer JD, Arner P, and Hotamisligil GS. Altered the adiponectin gene predict the conversion from impaired glucose
tumor necrosis factor-␣ (TNF-␣) processing in adipocytes and increased tolerance to Type 2 diabetes: the STOP-NIDDM trial. Diabetes 54:
expression of transmembrane TNF-␣ in obesity. Diabetes 51: 1876 – 893– 899, 2005.
1883, 2002. 120. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, and Friedman
113. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, JM. Positional cloning of the mouse obese gene and its human homo-
Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel logue. Nature 372: 425– 432, 1994.

J Appl Physiol • VOL 99 • AUGUST 2005 • www.jap.org