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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

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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
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.,

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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
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: potent inhibitor of carnitine palmitoyl transferase-1, the rate-
http://www. 8750-7587/05 $8.00 Copyright © 2005 the American Physiological Society 757
Invited Review

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-

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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 •

Invited Review
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

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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 •
Invited Review

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

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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 •
Invited Review
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