International Journal of Endocrinology

International Journal of Endocrinology / 2013 / Article
Special Issue

Adipocytokines, Metabolic Syndrome, and Exercise

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Review Article | Open Access

Volume 2013 |Article ID 801743 | 28 pages | https://doi.org/10.1155/2013/801743

The Effects of Exercise Training on Obesity-Induced Dysregulated Expression of Adipokines in White Adipose Tissue

Academic Editor: Eun Seok Kang
Received06 Jul 2013
Revised07 Oct 2013
Accepted10 Oct 2013
Published04 Dec 2013

Abstract

Obesity is recognized as a risk factor for lifestyle-related diseases such as type 2 diabetes and cardiovascular disease. White adipose tissue (WAT) is not only a static storage site for energy; it is also a dynamic tissue that is actively involved in metabolic reactions and produces humoral factors, such as leptin and adiponectin, which are collectively referred to as adipokines. Additionally, because there is much evidence that obesity-induced inflammatory changes in WAT, which is caused by dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein 1, contribute to the development of insulin resistance, WAT has attracted special attention as an organ that causes diabetes and other lifestyle-related diseases. Exercise training (TR) not only leads to a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the inflammation-related adipokines in WAT. Therefore, TR is widely used as a tool for preventing and improving lifestyle-related diseases. This review outlines the impact of TR on the expression and secretory response of adipokines in WAT.

1. Introduction

In recent years, obesity caused by the hypertrophy of white adipose tissue (WAT) has steadily increased worldwide, and has become a serious social problem [1]. In 2010, the Organization for Economic Cooperation and Development (OECD) released a report on the current state of obesity and the cost-effectiveness of preventive measures [2, 3]. That report states that obesity rates have risen in many countries, and that one in two individuals is either obese or overweight in about half of OECD countries. It is widely known that obesity is a risk factor for various “lifestyle-related diseases” such as type 2 diabetes and hypertension, and that obesity and diabetes cause increases in atherosclerotic disease. Therefore, there is an urgent need to establish strategies for the prevention and improvement of obesity and diabetes.

Epidemiological studies have shown that exercise is effective for preventing and improving obesity and diabetes [4, 5]. For example, a study by Helmrich et al. [6] followed 5,990 male graduates of the University of Pennsylvania over 14 years and found that the risk of developing diabetes is reduced by 6% for every 500 kcal increase in weekly exercise. Furthermore, a study that followed 21,271 male U.S. doctors over five years revealed that even a once-weekly bout of exercise at an intensity that is sufficient to cause sweating reduced the risk of developing diabetes [7]. In addition, results from a study that followed 87,253 female U.S. nurses over eight years showed that the group that exercised at least once a week at an intensity sufficient to cause sweating had a relative risk of developing diabetes of 0.84 compared with a group that exercised less than once a week [8].

Although WAT was once considered to be merely a site for energy storage, in recent years it has become better understood at the molecular level; for example, how WAT secretes physiologically active substances, collectively known as adipokines, and how obesity-induced dysregulated expression of adipokines in WAT causes insulin resistance, which is the pathogenesis of diabetes [911]. Therefore, WAT is considered to be one of the tissues that play a critical role in the onset of lifestyle-related diseases, and the reduction of excess WAT and the improvement of abnormal adipokine secretion are important strategies for the prevention and improvement of lifestyle-related diseases. Exercise training (TR) not only causes a loss of WAT mass, but can also influence the secretory response and expression of adipokines in WAT. This review outlines the impact of TR on the adipokines in WAT.

2. Adipokines and the Inflammatory Response of WAT

The major role of subcutaneous and visceral WAT is to supply and store energy via adipocytes in WAT. Most of the ingested excess energy is stored within adipocytes in the form of triglycerides, which are formed through the binding of glycerol and fatty acids. During exercise, catchecolamines (adrenaline and noradrenaline) secreted from the adrenal medulla or the sympathetic nerve terminal break down triglycerides within adipocytes, and the resultant fatty acids are carried to skeletal muscle via the blood [12]. However, following the discovery of leptin by Zhang et al. [13] in 1994, leptin was established as a hormone that is secreted by WAT, and a string of new humoral factors that are secreted by WAT were discovered. Therefore, the old concept of WAT as a mere storage site for energy has been revised to also acknowledge it as an endocrine organ. The humoral factors secreted from WAT are collectively referred to as adipokines (Figure 1).

In recent years, it has become clear that obesity is a chronic and mild systemic inflammatory condition, and there is much evidence that chronic inflammation of WAT contributes to the development of insulin resistance. This systemic inflammation has become closely acknowledged as the molecular basis of diabetes [911]. When adipocyte hypertrophy occurs due to excessive energy intake or lack of exercise, infiltration by macrophages, which are one type of immunocompetent cell, is observed in WAT. In WAT infiltrated by macrophages, the production of proinflammatory adipokines, such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1), is increased and the production of anti-inflammatory adiponectin is decreased, thereby causing chronic inflammation of WAT (Figure 2) [1416]. This increase in proinflammatory adipokines is not limited to WAT, but also promotes insulin resistance in skeletal muscle and liver as a paracrine agent. Thus, the inflammatory response plays an important role in WAT activity.

3. Representative Adipokines and the Effects of TR

3.1. Leptin

Leptin is a hormone that acts on leptin receptors (ob-R) in the hypothalamus to strongly suppress appetite and promote increased energy expenditure [1719]. There is strong ob-R expression in the arcuate nucleus, ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and lateral hypothalamic area of the hypothalamus [18]. Although the expression of mRNA for leptin is elevated in the WAT of obese humans and animals and blood levels also increase, since there is impaired leptin action called “leptin resistance”, leptin does not function sufficiently to suppress appetite or promote energy expenditure [18, 2022]. On the other hand, it is also known that leptin has inflammatory effects, such as increasing the expression of inflammatory cytokines involving TNF-α by acting on monocytes [9].

Evidence shows that seven weeks of spontaneous running TR reduces the expression of mRNA for leptin in the visceral and subcutaneous WAT of obese rats (Table 1) [23]. Additionally, other research indicates that even a short duration (four weeks) of spontaneous activity reduces leptin mRNA expression in rat WAT (Table 1) [24]. For obese humans, however, one study found that even 12 weeks of one-hour aerobic exercise sessions had no effect on the expression of mRNA for leptin in subcutaneous WAT (Table 1) [32]. On the other hand, there have been many studies on the effects of TR on the human blood levels of leptin (Table 2) [3450]. Many cases have shown that concentrations of leptin decrease with a reduction in WAT mass (Table 2) [34, 36, 4145, 47, 48]. By contrast, when no significant differences are observed in blood leptin levels after TR, neither is body fat reduced (Table 2) [34, 35, 39]. Therefore, the reduced blood concentration of leptin after TR is due more to the reduction in body fat caused by TR than to the effects of TR itself. Some studies, however, suggest that a longer duration (≥12 weeks) of TR or TR with caloric restriction can contribute to a reduction in blood leptin concentration that is independent of the influence of body fat reduction (Table 2) [34, 37, 40, 46].

(a) Animal studies

CitationExperimental animalsExercise programDiet restrictionDuration of interventionWAT used in experimentEffects of TR on expression of adipokines in WATChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

Zachwieja et al. [23]Diet-induced obesity sensitive ratsVoluntary wheel runningNone7 weeksEpididymal and inguinal WATEpididymal WAT  
Leptin mRNA: decrease ( )
Inguinal WAT  
Leptin mRNA: decreasing trend
Epididymal and inguinal FM: decrease
Diet-induced obesity resistant ratsVoluntary wheel runningNone7 weeksEpididymal and inguinal WATEpididymal WAT  
Leptin mRNA: decrease ( )
Inguinal WAT  
Leptin mRNA: decreasing trend
Epididymal and inguinal FM: decrease

Gollisch et al. [24]Rats chow dietVoluntary wheel running None4 weeksVisceral and subcutaneous WATVisceral WAT  
Leptin mRNA: decrease ( )
TNF-α mRNA and protein: NS
MCP-1 mRNA: NS
Adiponectin mRNA: NS
IL-6 mRNA: NS
Subcutaneous WAT  
Leptin mRNA: NS
TNF-α mRNA and protein: increase ( )
MCP-1 mRNA: NS
Adiponectin mRNA: NS
IL-6 mRNA: increase ( )
BM: NS; Visceral and subcutaneous FM: decrease
Rats HFDVoluntary wheel runningNone4 weeksVisceral and subcutaneous WATVisceral WAT  
Leptin mRNA: decrease ( )
TNF-α mRNA and protein: NS
MCP-1 mRNA: NS
Adiponectin mRNA: NS
IL-6 mRNA: NS
Subcutaneous WAT  
Leptin mRNA: decrease ( )
TNF-α mRNA: increase ( )
TNF-α protein: NS
MCP-1 mRNA: NS
Adiponectin mRNA: decrease ( )
IL-6 mRNA: increase ( )
BM: decrease; Visceral and subcutaneous FM: decrease

Bradley et al. [25]Mice chow diet Voluntary wheel running None10 weeks
(exercise: 6 weeks)
Perigonadal and mesenteric WATPerigonadal WAT  
TNF-α mRNA: decrease ( )
MCP-1 mRNA: decrease ( )
Mesenteric WAT  
MCP-1 mRNA: decrease ( )
BM and FM: decrease
Mice HFDVoluntary wheel runningNone10 weeks
(exercise: 6 weeks)
Perigonadal and mesenteric WAT Perigonadal WAT  
TNF-α mRNA: decrease ( )
MCP-1 mRNA: decrease ( )
Mesenteric WAT  
MCP-1 mRNA: decrease ( )
BM and FM: decrease

Vieira et al.
[26]
Mice HFDTreadmill running for 40 min/day on 5 times/week at 65–70%
O2 max
None18 weeks
(exercise: 6 or 12 weeks)
Epididymal and retroperitoneal WATExercise for 6 weeks  
Leptin mRNA: decreasing trend
TNF-α mRNA: NS
MCP-1 mRNA: NS
Exercise for 12 weeks  
Leptin mRNA: decreasing trend
TNF-α mRNA: decrease ( )
MCP-1 mRNA: decrease ( )
Exercise for 6 weeks  
BM and epididymal FM: decrease
Exercise for 12 weeks  
BM and epididymal FM: decrease

Sakurai et al. [27]Rats chow dietTreadmill running on 5 times/week. On the first day of training, all rats ran for 30 min at 15 m/min, and then running time and velocity were extended until rats were running for 90 min at 30 m/min.None9 weeksEpididymal WATTNF-α protein: decrease ( )BM and epididymal FM: decrease

Sakurai et al. [28]Rats chow dietTreadmill running on 5 times/week. On the first day of training, all rats ran for 30 min at 15 m/min, and then running time and velocity were extended until rats were running for 90 min at 30 m/min. None9 weeksEpididymal, retroperitoneal, and subcutaneous WATEpididymal adipocyte  
TNF-α mRNA: decrease ( )
MCP-1 mRNA: decrease ( )
Epididymal WAT  
TNF-α protein: decrease ( )
MCP-1 protein: decrease ( )
Retroperitoneal WAT  
TNF-α protein: decreasing trend
MCP-1 protein: decrease ( )
Subcutaneous WAT  
TNF-α protein: NS
MCP-1 protein: decrease ( )
BM: decrease  
epididymal, retroperitoneal, and subcutaneous % BFM: decrease

Lira et al. [29]Rats chow dietTreadmill running on 5 times/week at 55–65% O2 max. On the first day of training, all rats ran for 30 min. On the subsequent days of training, running time was extended 10 min each day until rats were running 60 min/day.None9 weeksRetroperitoneal and mesenteric WATRetroperitoneal WAT  
TNF-α protein: NS
Mesenteric WAT  
TNF-α protein: increase ( )
BM and retroperitoneal FM: decrease
Mesenteric FM: NS

Nara et al. [30]Rats high-sucrose
diet
Voluntary wheel runningNone4 and 12 weeksMesenteric and subcutaneous WATMesenteric WAT  
Exercise for 4 and 12 weeks  
TNF-α mRNA: increase ( )
TNF-α protein: increase ( )
Subcutaneous WAT  
Exercise for 4 and 12 weeks  
TNF-α mRNA: NS
TNF-α protein: NS
Exercise for 4 weeksBM: NS
Mesenteric and subcutaneous FM: NS
Exercise for 12 weeks
BM: NS
Mesenteric and subcutaneous FM: decrease

Miyazaki et al. [31]Rats chow dietTreadmill running on 5 times/week. On the first day of training, all rats ran for 30 min at 15 m/min, and then running time and velocity were extended until rats were running for 90 min at 30 m/min.None9 weeksEpididymal, retroperitoneal, and inguinal WATEpididymal adipocyte  
Leptin mRNA: NS
Adiponectin mRNA: increase ( )
Retroperitoneal adipocyte  
Leptin mRNA: NS
Adiponectin NS
Inguinal adipocyte  
Leptin mRNA: NS
Adiponectin mRNA: increase ( )
BM: decrease  
epididymal, retroperitoneal, and inguinal FM: decrease

(b) Human studies

CitationSubjects Exercise programDiet restrictionDuration of interventionWAT used in experimentEffects of TR on expression of adipokines in WATChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

Christiansen et al. [32] Obese exercise (9 m, 10 f)Aerobic exercise for 65–75 min on 3 times/week (energy expenditure of 500–600 kcal/session)None12 weeksAbdominal subcutaneous WATLeptin mRNA: NS
TNF-α mRNA: NS
MCP-1 mRNA: NS
Adiponectin mRNA: increase ( )
IL-6 mRNA: NS
BM and BMI: NS
Changes in body weight after intervention were 3.5%

Christiansen et al. [32]Obese exercise + hypocaloric diet (10 m, 11 f)Same as aboveVery low energy diet (800 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksAbdominal subcutaneous WATLeptin mRNA: decrease ( )
TNF-α mRNA: NS
MCP-1 mRNA: NS
Adiponectin mRNA: increase ( )
IL-6 mRNA: NS
BM and BMI: NS  
changes in body weight after intervention were 11.1%
Obese hypocaloric diet (10 m, 9 f)NoneVery low energy diet (600 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksAbdominal subcutaneous WATLeptin mRNA: decrease ( )
TNF-α mRNA: NS
MCP-1 mRNA: NS
Adiponectin mRNA: increase ( )
IL-6 mRNA: NS
BM and BMI: NS  
changes in body weight after intervention were 10.5%

Bruun et al. [33]Obese (11 m, 12 f)Exercise training consisted of at least 2-3 h of moderate intensity physical activity (e.g., walking, swimming, aerobics) on 5 times/weekHypocaloric diet calculated to reduce the subject’s body
weight by ~1%/week
15 weeksAbdominal subcutaneous WATTNF-α mRNA: decrease ( )
MCP-1 mRNA: NS
Adiponectin mRNA: increase ( )
IL-6 mRNA: decrease ( )
BM, BMI, and FM: decrease

Results are reported as mean ± SD or SE; P value reported for sedentary control group versus exercise trained group or pre- versus postvalues. f: female; HFD: high fat diet; m: male; NS: not significant; O2 max: maximal oxygen uptake; WAT: white adipose tissue.

Citation , genderGroupExercise programDiet restrictionDuration of interventionPreleptin (ng/mL)Postleptin (ng/mL)P valueChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

Aerobic exercise

Houmard et al. [35]7 m, 9 fYounger leanCycle ergometer at 70–75% O2 max for 60 minNone7 days7.1 ± 1.37.6 ± 1.3NSBM: NS
6 m, 8 fOlder subjects with relatively more adipose tissue Same as aboveNone7 days14.2 ± 2.711.0 ± 1.3NSBM: NS

Halle et al.
[36]
20 mObese with T2DMCycle ergometer for 30 min on 5 times/week at 70% HRM (1,100 kcal/wk)Diet consisted of a 1,000-kcal diabetic diet with a carbohydrate content of ~50%, a fat content of 25%, and a protein content of 25%4 weeks7.9 ± 4.45.6 ± 3.5 BMI: decrease

Ishii et al. [37]9 m, 14 fT2DM exercise training with diet therapyWalking and cycle ergometer exercise at 50% of O2 max for 60 min on at least 5 times/week 25- to 27-kcal/kg/day diet (54% to 58% carbohydrate, 22% to 24% protein, 18% to 20% fat)6 weeks7.2 ± 3.64.6 ± 2.5 BM, BMI, and % BFM: NS
11 m, 16 fT2DM diet therapy aloneNoneSame as above6 weeks6.9 ± 3.45.6 ± 2.9NSBM, BMI, and % BFM: NS

Boudou et al. [38]8 mT2DM controlNoneNone8 weeks7.26 ± 3.857.40 ± 3.95NSBM and BMI: NS; Visceral and
subcutaneous adipose tissue (cm2): NS
8 mT2DM exerciseEndurance exercise (75% VO2 peak, 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO2 peak separated by 3 min exercises at 50% VO2 peak) once a week, on a cycle ergometerNone8 weeks6.05 ± 4.605.60 ± 4.30NSBM and BMI: NS; Visceral and
subcutaneous adipose tissue (cm2): decrease

Kraemer et al. [39]14 fOverweight controlNoneNone9 weeks33.24 ± 3.7834.69 ± 3.14NSBM, BMI, and % BFM: NS
16 fOverweight exerciseThree-four times/week of four 20–30 min/session. Two of the exercise days consisted of step aerobics and 1-2 of the exercise days consisted of treadmill or stationary cycle exerciseNone9 weeks28.0 ± 2.1331.04 ± 2.71NSBM, BMI, and % BFM: NS

Hickey et al. [40]9 mMiddle aged sedentary Exercise training consists of overground and/or treadmill walking and/or running for 45 min on 4 times/week at 85% HRMNone12 weeksNSBM, FM, and % FM: NS
9 fMiddle aged sedentarySame as aboveNone12 weeksDecrease of 17.5% BM, FM, and % FM: NS

Ozcelik et al. [41]14 f ObeseCycle ergometer for approximately 45 min on 3-4 times/week. Training exercise intensity was established using the anaerobic threshold.None12 weeks23.62 ± 3.513.13 ± 3.4 BM, BMI, and FM: decrease

Polak et al.
[42]
25 f Obese premenopausalAerobic exercise (aerobic exercise performed in gymnasium and cycleergometer) for 45 min on 5 times/week at 50% O2 max None12 weeks24.3 ± 8.718.1 ± 8.3 BM, BMI, and % BFM: decrease

Okazaki et al. [43]15 fObeseCycle ergometer or indoor walking for 30 min and low-impact aerobics for 30 min at 50% O2 maxMild hypocalbolic diet12 weeks14.7 ± 5.38.9 ± 3.6 BM, BMI, and FM: decrease
26 fNonobeseSame as aboveSame as above12 week7.6 ± 3.95.6 ± 2.2 BM, BMI, and FM: decrease

Pérusse et al. [44]51 mSedentary adultThe subjects worked on cycle ergometer at an intensity corresponding to 55% of O2 max for 30 min per session at the beginning, increasing progressively toward an intensity of 75% of O2 max for 50 min during the last 6 weeks of the training protocol.None20 weeks4.6 ± 4.43.9 ± 4.2 BMI: NS; FM and % BFM: decrease
46 fSame as aboveNone20 weeks11.9 ± 8.512.4 ± 8.1NSBMI, FM, and % BMF: NS

Kondo et al. [45]8 fNonobese controlNoneNone7 months6.7 ± 1.26.5 ± 2.2NSBM, BMI: NS; FM and % BFM: decrease
8 fObeseExercise training (fast slope walking, slope jogging, dumbbells, stretching, leg cycling, and jumping rope) for 30–60 min at 60–70% HRR on 4-5 times/weekNone7 months16.4 ± 4.612.3 ± 5.4 BM, BMI, FM, and % BFM: decrease

Reseland et al. [46]37 mMS controlNoneNone1 year12.0 ± 10.10.5 ± 4.6
(Change)
NSBMI, FM, and % BFM: NS
44 mMS dietNoneDietary counseling1 year8.7 ± 4.3−0.7 ± 3.0 BMI, FM, and % BFM: decrease
48 mMS exerciseEndurance exercise (aerobics, circuit training, and fast walking) and jogging for 60 min on 3 times/week None1 year9.8 ± 4.9−0.4 ± 2.3NSBMI: NS; FM and % BFM: decrease
57 mMS diet + exerciseSame as aboveDietary counseling1 year9.1 ± 6.2−2.2 ± 2.4 BMI, FM, and % BFM: decrease

Miyatake et al. [47]36 mOverweightAerobic exercise (walking, aerobic dance, and swimming) and resistance training (leg extension and leg flexion) for 90 min at 50–65% HRMNone1 year6.7 ± 4.05.1 ± 3.1 BM, BMI, FM, and % BFM: decrease

Hsieh and Wang [48] 22 m, 30 fYounger T2DMEndurance exercise for 20 min at 50–74% HRMSubjects were prescribed a diet with 500 kcal/day deficit.1 year17.62 ± 3.1814.00 ± 3.16 BMI, and % BFM: decrease
20 m, 30 fOlder T2DMSame as aboveSame as above1 year17.81 ± 2.1512.63 ± 2.09 BMI, and % BFM: decrease

Resistance exercise

Ryan et al.
[49]
8 fNonobese postmenopausal women RTThree exercise sessions/week on pneumatic variable resistance machinesNone16 weeks14.6 ± 3.314.8 ± 3.0NSBM, BMI, FM, and % BFM: NS
7 fObese postmenopausal women RT + WLSame as aboveDietary counseling and energy restriction (hypocaloric diets)16 weeks22.9 ± 3.914.6 ± 2.6 BM, BMI, FM, and % BFM: decrease



Fatouros et al. [50]
10 mOverweight elderly controlNoneNone24 weeks9.5 ± 0.89.4 ± 0.7NSBM and BMI: NS
14 mOverweight elderly low-intensity RTRT for approximately 60 min on 3 times/week at 45–50% of 1RMNone24 weeks9.1 ± 0.78.8 ± 0.7 BM: NS; BMI: decrease
12 mOverweight elderly moderate-
intensity RT
RT for approximately 60 min on 3 times/week at 60–65% of 1RMNone24 weeks8.9 ± 0.68.7 ± 0.4 BM: NS; BMI: decrease
14 mOverweight elderly high-
intensity RT
RT for approximately 60 min on 3 times/week at 80–85% of 1RMNone24 weeks9.7 ± 0.67.8 ± 0.6 BM: NS; BMI: decrease

Results are reported as mean ± SD or SE; P value reported for pre- versus postvalues. f: female; HRM: heart rate maximum; m: male; NS: not significant; RM: repetition maximum; RT: resistance training; T2DM: type 2 diabetes; O2 max: maximal oxygen uptake; WL: weight loss.

Several studies have also concentrated on the effects of resistance training, such as the bench press exercise, on blood leptin levels (Table 2). One study on postmenopausal obese women found that after performing three days a week of resistance training using machines and restricting diet for 16 weeks, blood leptin levels were decreased compared with pretraining levels, but that resistance training alone had no effect on leptin [49]. However, when elderly individuals were divided into low intensity (45–50% 1 repetition maximum [RM]), moderate intensity (60–65% 1 RM), and high intensity (80–85% 1 RM) groups and performed 60-minute exercise sessions three times a week for six months, blood leptin levels were lower in all the groups compared with the respective pretraining levels, and the magnitude of this decrease was significantly greater in the high intensity group than in the low and moderate intensity groups [50]. Furthermore, although blood leptin levels were higher at six months after the end of training than immediately after the end of training, the levels remained significantly lower than their pretraining values in the high intensity group [50].

3.2. TNF-α

Since the discovery that gene expression of the major inflammatory cytokine TNF-α is elevated in WAT in animal models of obesity, there have been many studies on its involvement in insulin resistance and its other actions [51, 52]. Expression of TNF-α increases not only in the WAT of obese animals, but also in that of obese humans; that is, TNF-α has a strong positive correlation with body mass index (BMI) and blood insulin levels [5355]. TNF-α weakens insulin signaling by insulin receptor substrate 1-mediated inhibition of insulin receptor tyrosine kinase activity in areas such as skeletal muscle and causes reduced expression of glucose transporters and adiponectin in adipocytes, which contributes to the development of insulin resistance [5658].

There is no clear consensus regarding the effects of TR on TNF-α in WAT (Table 1). For example, increased expression of TNF-α in visceral WAT in mice that became obese after six weeks of consuming a high-fat diet can be suppressed by spontaneous running [25, 26]. Additionally, our studies showed that nine weeks of treadmill running decreased the TNF-α protein content of the rat WAT [27, 28], but some results have shown a contrasting increase after TR [24, 29, 30]. Studies regarding obese individuals have also examined the effects of TR on TNF-α expression in WAT. Although one study found that TNF-α expression in the subcutaneous WAT of severely obese male and female adults decreased after 15 weeks of performing TR, such as walking for five days a week and undergoing diet therapy; a conflicting study on obese adults found that there was no change in TNF-α mRNA expression in subcutaneous WAT even when weight or body fat decreased after 12 weeks of aerobic exercise [32, 33].

There are also conflicting results for the blood concentrations of TNF-α (Table 3) [33, 42, 45, 5963]. A study on diabetic patients showed that although there is no change in blood TNF-α concentration after four weeks of dietary restrictions and walking TR in nonobese diabetic patients, the concentration decreased in obese patients [59]. Furthermore, when obese adult women exercised on a bicycle ergometer for 30 minutes a day, five days a week at 70% max for 12 weeks, decreases in blood concentrations of both TNF-α and soluble TNF receptor 2 were observed in both the women with insulin resistance and those without [60]. In another study, however, a 15-week combination of diet therapy and TR did not affect the TNF-α level in obese individuals [33]. In yet another study, 12 weeks of endurance TR actually increased the blood concentration of TNF-α in adult women [61].

(a) TNF-α

Citationn, genderGroupExercise programDiet restrictionDuration of interventionPre-TNF-α (pg/mL)Post-TNF-α  (pg/mL)P valueChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

Katsuki et al. [59]11 m, 1 fNonobese NIDDMWalking about 15,000 steps dailyDietary treatment (1400–1720 kcal/day with a diet consisting of 20 energy percent (en%) protein, 25 en% fat, and 55 en% carbohydrates4 weeksNSBMI and visceral adipose tissue area (cm2): decrease;
subcutaneous adipose tissue (cm2): NS
11 m, 1 fObese-NIDDMSame as aboveSame as above4 weeksDecrease BMI, visceral and subcutaneous adipose tissue area (cm2): decrease;

Stŗczkowski et al. [60]8 fObese with normal glucose
tolerance
Cycle ergometer for 30 min on 5 times/week at 70% HRMNone12 weeks3.88 ± 0.493.27 ± 0.54 BM, BMI, FM, and % BFM: decrease
8 fObese with impaired glucose
tolerance
Same as aboveNone12 weeks6.59 ± 2.315.15 ± 1.19 BM, BMI, and % BFM: decrease

Polak et al.
[42]
25 f Obese premenopausalAerobic exercise (aerobic exercise performed in gymnasium and cycleergometer) for 45 min on 5 times/week at 50% O2 max None12 week6.1 ± 7.64.8 ± 4.5 BM, BMI, and % BFM: decrease

Bruun et al. [33]11 m, 12 fObeseExercise training consisted of at least 2-3 h of moderate intensity physical activity (e.g., walking, swimming, aerobics) on 5 times/weekHypocaloric diet calculated to reduce the subject’s body
weight by ~1%/week
15 weeks1.0 ± 0.081.0 ± 0.2NSBM, BMI, and FM: decrease

Kondo et al. [45]8 fNonobese controlNoneNone7 months2.3 ± 0.92.1 ± 1.4NSBM, BMI: NS; FM and % BFM: decrease
8 fObeseExercise training (fast slope walking, slope jogging, dumbbells, stretching, leg cycling, and jumping rope) for 30–60 min at 60–70% HRM on 4-5 times/weekNone7 months7.6 ± 2.34.8 ± 1.2 BM, BMI, FM, and % BFM: decrease

   
   
   
   
   
   
   
   
   
   
Horne et al. [61]
7 mHealthy endurance trainingCycle ergometers 2 times/week for 30 min and progressed to 42 min (a 4-min increase every 4 weeks) at a power output equivalent to that at ventilation thresholdNone12 weeks5.7 ± 4.46.0 ± 4.0
(6 weeks)
5.9 ± 2.7
(12 weeks)
NS
4 fSame as aboveNone12 weeks5.6 ± 3.737.8 ± 24.7a  
(6 weeks)
17.6 ± 6.4b  
(12 weeks)
a   
(versus pre)
b   
(versus pre and 6 weeks)
7 mHealthy resistance trainingResistance training by using machine on 3 times/weekNone12 weeks9.5 ± 3.010.8 ± 4.6
(6 week)
5.8 ± 2.9
(12 week)
NS
4 fSame as aboveNone12 weeks2.8 ± 2.06.6 ± 4.08
(6 weeks)
0.3 ± 0.5
(12 weeks)
NS
8 mHealthy endurance and resistance training Combination of above endurance and resistance training None12 weeks2.3 ± 1.9
4.7 ± 0.5
(6 weeks)
5.6 ± 2.9
(12 weeks)
NS
5 fSame as aboveNone12 weeks4.5 ± 2.0
8.0 ± 4.0
(6 weeks)
4.5 ± 0.5
(12 weeks)
NS

Kohut et al.
[62]
40Overweight aerobic exercise with or without β-blocker treatmentAerobic exercise for 45 min on 3 times/weekNone10 monthsDecreaseMain effect of time, BMI: NS
47Over weight flexibility/strength exercise with or without β-blocker treatmentFlexibility/strength exercise for 45 min on 3 times/weekNone10 monthsDecreaseMain effect of time, BMI: NS

   
   
   
   
   
   
   
   
   
   
   
   
Nicklas et al. [63]
Base line: 70
6 months: 63:
18 months: 60
Overweight or obese older controlNoneNone18 months3.8 ± 7.5Changes
−0.74 ± 3.7
(6 months)
−0.77 ± 3.7
(18 months)
NSBM: NS
Base line: 67
6 months: 58:
18 months: 53
Overweight or obese exerciseExercise program consisted of an aerobic phase (15 min), a resistance-training phase (15 min), a second aerobic phase (15 min), and a cool-down phase (15 min) on 3 times/week.None18 months3.4 ± 0.8Changes
−0.69 ± 5.8
(6 months)
0.28 ± 6.3
(18 months)
NSBM: NS
Base line: 71
6 months: 63:
18 months: 53
Overweight or obese dietary WLNone Counseling to decrease their energy intake by 500 kcal/day18 months2.5 ± 1.8Changes
−0.23 ± 1.8
(6 months)
0.64 ± 5.9
(18 months)
NSBM: decrease
Base line: 64
6 months: 58
18 months: 53
Overweight or obese exercise + dietary WLExercise program consisted of an aerobic phase (15 min), a resistance-training phase (15 min), a second aerobic phase (15 min), and a cool-down phase (15 min) on 3 times/week.Same as above18 months3.4 ± 6.4Changes
−0.46 ± 3.7
(6 months)
−0.72 ± 4.6
(18 months)
NSBM: decrease

(b) MCP-1

Citationn, genderGroupExercise programDiet restrictionDuration of interventionPre-MCP-1 (pg/mL)Post-MCP-1 (pg/mL)P valueChanges of BM, BMI, FM, and % BFM

Trøseid et al. [64]14MS with or without administration of pravastatin controlNoneNone12 weeks−2.0 (the changes from baseline in plasma levels of MCP-1)NSBMI: NS
18MS with or without administration of pravastatin exerciseThe duration of each workout was 45–60 min. Approximately 40% of the scheduled workout was walking/jogging/cycling and 60% was strength training. The strength training was performed in cycles with 15–20 repetitions per cycle, and large muscle groups such as thighs, back, and abdomen were trained.None12 weeks−50 BMI: decrease

   
   
   
   
   
   
   
   
Christiansen et al. [32]
9 m, 10 fObese exerciseAerobic exercise for 65–75 min on 3 times/week (energy expenditure of 500–600 kcal/session)None12 weeksDecreasing trend (Relative changes) BM and BMI: NS
Changes in body weight after intervention were 3.5%
10 m, 11 fObese exercise + hypocaloric dietSame as aboveVery low energy diet (800 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksDecrease BM and BMI: NS
Changes in body weight after intervention were 11.1%
10 m, 9 fObese hypocaloric dietNoneVery low energy diet (600 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksDecrease BM and BMI: NS
Changes in body weight after intervention were 10.5%

Bruun et al. [33]11 m, 12 fObeseExercise training consisted of at least 2-3 h of moderate intensity physical activity (e.g., walking, swimming, aerobics) on 5 times/weekHypocaloric diet calculated to reduce the subject’s body
weight by ~1%/week
15 weeks141.2 ± 8.3122.0 ± 6.3 BM, BMI, and FM: decrease

Results are reported as mean ± SD or SE; P value reported for pre- versus post values. f: female; HRM: heart rate maximum; m: male; MS: metabolic syndrome; NIDDM: noninsulin dependent diabetes mellitus; NS: not significant; RM: repetition maximum; O2 max: maximal oxygen uptake; WL: weight loss.
3.3. MCP-1

MCP-1, which is identified as a monocyte chemotactic factor, shows increased expression in the WAT of obese mice, and elevated MCP-1 contributes to inflammatory changes by inducing macrophage infiltration into WAT via its receptor, C-C chemokine receptor-2, which is expressed in monocytes and macrophages [70, 71]. In mice that are genetically modified to only express MCP-1 excessively in adipocytes, infiltration into visceral WAT by macrophages is elevated when compared with control mice, and there is increased expression of macrophage markers and TNF-α genes in the tissue, as well as increased insulin resistance [70, 71]. Mice that consume a high-fat diet show increased expression of MCP-1 mRNA in visceral WAT, but this expression is suppressed by six weeks of spontaneous running activity (Table 1) [25]. Additionally, other studies where mice both consumed a high-fat diet and underwent treadmill running, MCP-1 mRNA expression, which had increased due to the mice’s high-fat diet, was reduced by TR (Table 1) [26]. Moreover, nine weeks of treadmill running has reduced MCP-1 protein levels in rat subcutaneous and visceral WAT (Table 1) [27]. However, there were no changes in expression of mRNA for MCP-1 either in the subcutaneous and visceral WAT of rats that performed four weeks of spontaneous running or in the subcutaneous WAT of obese humans who performed 12 weeks of aerobic exercise (Table 1) [24, 32].

There seems to be consensus that TR diminishes blood levels of MCP-1 (Table 3). The blood concentration of MCP-1 was reduced in rats by nine weeks of treadmill running TR [27]. Studies on human patients with metabolic syndrome [64] and obese individuals [32] have also shown reductions and downward trends in MCP-1 after 12 weeks of TR. A 15-week combination of TR and diet therapy also reduced the blood concentration of MCP-1 in obese individuals [33].

3.4. Adiponectin

Adiponectin increases fatty acid oxidation and glucose uptake in skeletal muscle and inhibits gluconeogenesis in the liver [72, 73]. Adiponectin also inhibits the expression and secretion of TNF-α in macrophages and increases the production of anti-inflammatory cytokines such as interleukin (IL)-10 [74]. Therefore, adiponectin is thought to have anti-inflammatory effects. In accordance with that function, the expression of mRNA for adiponectin is reduced in the WAT of genetically obese mice and obese humans, and both obese individuals and diabetic patients have a lower blood concentration compared with healthy individuals [75, 76]. Insulin resistance and hypertension are improved when KKAy mice (mouse models of obesity and diabetes) are administered physiological concentrations of adiponectin, and insulin resistance is observed in KO mice deficient in adiponectin, suggesting that obesity-induced decreases in adiponectin expression in WAT are closely associated with the development of insulin resistance and the onset of diabetes [72, 73].

A 15-week combination of TR and diet therapy or 12 weeks of aerobic exercise has shown increases in the expression of mRNA for adiponectin in the subcutaneous WAT of obese individuals (Table 1) [32, 33]. In studies on rats, nine weeks of treadmill running has increased the mRNA expression in visceral and subcutaneous adipocytes (Table 1) [31]. In at least one study, short periods of consuming a high-fat diet increased adiponectin expression in the subcutaneous WAT of rats, and TR by spontaneous running activity suppressed this increase. That study found no effect of TR on adiponectin mRNA expression in visceral WAT (Table 1) [24].

As with leptin, there have been many studies on the effects of TR on the blood levels of adiponectin (Table 4) [32, 33, 38, 42, 45, 50, 6569]. Although most indicate that there is no change, some studies show that it increases, so there is no consensus on this point. Hulver et al. [69] found that the blood concentration of adiponectin did not change after obese adults performed aerobic exercises such as running at 65–85% max four times a week over a period of six months. Another study on diabetic men also found no change in the blood concentration of adiponectin after eight weeks of performing aerobic exercise three times a week, even though the amount of visceral fat decreased [38]. Even after elderly obese men and women performed TR for 60 minutes on a treadmill or bicycle ergometer at 80–85% of their maximum heart rate five times a week for 12 weeks, there was no change in the blood concentration of adiponectin despite the deceases in BMI and body fat [67]. Contrary studies have found that 60 minutes of TR, such as running performed four times a week for four weeks, has led to increases in the blood concentration of adiponectin along with decreases in body fat in diabetics and individuals presenting impaired glucose tolerance [65]. In a similar manner, the blood concentration of adiponectin has been increased along with reduced BMI and body fat mass after seven months of TR such as slope jogging and dumbbells performed four to five times a week in obese young women [45].


Citation , genderGroupExercise programDiet restrictionDuration of interventionPreadiponectin (μg/mL)Postadiponectin (μg/mL)P valueChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

Aerobic exercise

   
   
   
Blüher et al. [65]
9 m, 11 fNormal glucose tolerance Exercise training consisted of 20 min of warming and cool-down periods,
20 min of running or biking, and 20 min of swimming on 3 times/week
None4 weeks8.7 ± 0.69.8 ± 0.6 BM, BMI, and % BFM: decrease
9 m, 11 fImpaired glucose toleranceSame as aboveNone4 weeks3.4 ± 0.266.7 ± 0.7 BM, BMI, and % BFM: decrease
11 m, 9 fT2DMSame as aboveNone4 weeks3.5 ± 0.46.5 ± 0.6 BM, BMI, and % BFM: decrease

   
   
   
Oberbach et al. [66]
9 m, 11 fNormal glucose tolerance Exercise training consisted of 20 min warming and cool-down periods,
20 min of running or biking, and 20 min of powertraining
None4 weeksNSBM, BMI, and % BFM: decrease
9 m, 11 fImpaired glucose toleranceSame as aboveNone4 weeksIncrease BM, BMI, and % BFM: decrease
11 m, 9 fT2DMSame as aboveNone4 weeksIncrease BM, BMI, and % BFM: decrease

   
   
   
   
Boudou et al. [38]
8 mT2DM controlNoneNone8 weeks7.30 ± 2.557.05 ± 2.10NSBM and BMI: NS; visceral and
subcutaneous adipose tissue area (cm2): NS
8 mT2DM exerciseEndurance exercise (75% VO2 peak, 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO2 peak separated by 3 min exercises at 50% VO2 peak) once a week, on a cycle ergometerNone8 weeks6.30 ± 2.756.00 ± 3.50NSBM and BMI: NS; visceral and
subcutaneous adipose tissue area (cm2): decrease

   
   
   
   
O'Leary et al. [67]
4 m, 7 fOlder insulin-resistant exercise + hypocaloric dietAerobic exercise for 60 min at 80–85% HRM on 5 times/weekDiet with total energy content calculated to
reduce body weight by 10–15% (~1,300 kcal/day).
12 weeks7.6 ± 0.96.6 ± 1.0NSBM, BMI, and FM: decrease
3 m, 7 fOlder insulin-resistant exercise + eucaloric dietSame as aboveWeight maintenance diet that consisted of their usual food consumption (~1,800 kcal/day)7.7 ± 1.26.8 ± 1.6NSBM, BMI, and FM: decrease

Polak et al.
[42]
25 f Obese premenopausalAerobic exercise (aerobic exercise performed in gymnasium and cycleergometer) for 45 min on 5 times/week at 50% O2 max None12 weeks10.9 ± 6.110.0 ± 4.4NSBM, BMI, and % BFM: decrease

Nassis et al.
[68]
21 fOverweight/obese girlsAerobic training for 40 min (10 min of warm up, 25 min of physical training games, and 5 minutes of cool down) on 3 times/weekNone12 weeks9.57 ± 3.019.08 ± 2.32NSBM, BMI, and % BFM: NS

   
   
   
   
   
   
Christiansen et al. [32]
9 m, 10 fObese exerciseAerobic exercise for 65–75 min on 3 times/week (energy expenditure of 500–600 kcal/session)None12 weeksNSBM and BMI: NS
Changes in body weight after intervention were 3.5%
10 m, 11 fObese exercise + hypocaloric dietSame as aboveVery low energy diet (800 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksIncrease BM and BMI: NS
Changes in body weight after intervention were 11.1%
10 m, 9 fObese hypocaloric dietNoneVery low energy diet (600 kcal/day) for 8 weeks followed by a weight maintenance diet for 4 weeks12 weeksIncrease BM and BMI: NS
Changes in body weight after intervention were 10.5%

Bruun et al. [33]11 m, 12 fObeseExercise training consisted of at least 2-3 h of moderate intensity physical activity (e.g., walking, swimming, aerobics) on 5 times/weekHypocaloric diet calculated to reduce the subject’s body
weight by ~1%/week
15 weeks5.2 ± 0.66.9 ± 0.5 BM, BMI, and FM: decrease

   
   
Hulver et al. [69]
8 m, 3 fNonobese exerciseTreadmill walking/running, stair climbing, and cycling for 45 min at 65–80% O2 max on 4 times/weekNone6 months6.3 ± 1.56.6 ± 1.8NSBM, BMI, and FM: NS
3 m, 11 fObese weight lossNoneGastric bypass surgery6 months4.4 ± 0.813.6 ± 2.2 BM and BMI: decrease

   
   
   
   
Kondo et al. [45]
8 fNonobese controlNoneNone7 months8.3 ± 1.58.2 ± 2.3NSBM, BMI: NS; FM and % BFM: decrease
8 fObeseExercise training (fast slope walking, slope jogging, dumbbells, stretching, leg cycling, jumping rope) for 30–60 min at 60–70% HRM on 4-5 times/weekNone7 months2.4 ± 1.34.2 ± 1.2 BM, BMI, FM, and % BFM: decrease

   
   
Hsieh and Wang [48]
22 m, 30 fYounger T2DMEndurance exercise for 20 min at 50–74% HRMSubjects were prescribed a diet with 500 kcal/day deficit.1 year4.13 ± 0.885.47 ± 0.59 BMI, and % BFM: decrease
20 m, 30 fOlder T2DMSame as aboveSame as above1 year4.26 ± 0.976.56 ± 0.86 BMI, and % BFM: decrease

Resistance exercise

   
   
   
   
   
   
   
Fatouros et al. [50]
10 mOverweight elderly controlNoneNone24 weeks7.22 ± 2.77.84 ± 3.5NSBM and BMI: NS
14 mOverweight elderly low-
intensity RT
Resistance training for approximately 60 min on 3 times/week at 45–50% of 1RMNone24 weeks7.45 ± 2.38.48 ± 2.2NS
BM: NS; BMI: decrease
12 mOverweight elderly moderate-
intensity RT
Resistance training for approximately 60 min on 3 times/week at 60–65% of 1RMNone24 weeks7.79 ± 1.49.48 ± 1.1 BM: NS; BMI: decrease
14 mOverweight elderly high-
intensity RT
Resistance training for approximately 60 min on 3 times/week at 80–85% of 1RMNone24 weeks7.04 ± 1.611.36 ± 1.6 BM: NS; BMI: decrease

Results are reported as mean ± SD or SE; P value reported for pre- versus post values. f: female; HRM: heart rate maximum; m: male; NS: not significant; RM: repetition maximum; RT: resistance training T2DM: type 2 diabetes; O2 max: maximal oxygen uptake.
3.5. IL-6

IL-6 is a cytokine that has a variety of functions such as regulating hematopoiesis, immune response, and inflammatory response. This cytokine also is known to have anti-inflammatory effects, and may have both proinflammatory and anti-inflammatory properties [77, 78]. Diabetic and obese individuals have high blood concentrations of IL-6, and its mRNA expression is elevated in the subcutaneous adipocytes of individuals presenting insulin resistance. Furthermore, IL-6 acts on adipocytes to inhibit insulin signaling [79, 80].

Many studies show that IL-6 levels increase in response to acute exercise; for instance, a single bout of exercise has increased the blood concentration of IL-6 more than 100 times. However, this increase in blood concentration was not due to increased production by WAT, but rather by increased production in skeletal muscle, an organ that produces IL-6 [78, 81]. A 15-week combination of TR and diet therapy reduces the expression of mRNA for IL-6 in the subcutaneous WAT of obese individuals (Table 1) [33]. However, although some studies show that the blood concentration of IL-6 decreases after TR, other studies have shown no change, so yet again there is no consensus (Table 5) [33, 42, 62, 63, 66, 68, 78].


Citation , genderGroupExercise programDiet restrictionDuration of interventionPre-IL-6 (pg/mL)Post-IL-6 (pg/mL)P valueChanges of body mass (BM), body mass index (BMI), fat mass (FM), and % body fat mass (% BFM)

   
   
   
Oberbach et al. [66]
9 m, 11 fNormal glucose tolerance Exercise training consisted of 20 min warming and cool-down periods,
20 min of running or biking, and 20 min of powertraining
None4 weeksNSBM, BMI, and %BFM: decrease
9 m, 11 fImpaired glucose toleranceSame as aboveNone4 weeksNSBM, BMI, and % BFM: decrease
11 m, 9 fT2DMSame as aboveNone4 weeksNSBM, BMI, and % BFM: decrease

Polak et al.
[42]
25 f Obese premenopausalAerobic exercise (aerobic exercise performed in gymnasium and cycleergometer) for 45 min on 5 times/week at 50% O2 max None12 weeks3.1 ± 3.71.4 ± 1.5NSBM, BMI, and % BFM: decrease

Nassis et al.
[68]
21 fOverweight/obese girlsAerobic training for 40 min (10 min of warm up, 25 min of physical training games, and 5 minutes of cool down) on 3 times/weekNone12 weeks1.67 ± 1.291.65 ± 1.25NSBM, BMI, and % BFM: NS

Bruun et al. [33]11 m, 12 fObeseExercise training consisted of at least 2-3 h of moderate intensity physical activity (e.g., walking, swimming, aerobics) on 5 times/weekHypocaloric diet calculated to reduce the subject’s body
weight by ~1%/week
15 weeks4.6 ± 0.63.4 ± 0.6 BM, BMI, and FM: decrease

   
   
   
Kohut et al.
[62]
40Overweight aerobic exercise with or without β-blocker treatmentAerobic exercise for 45 min on 3 times/weekNone10 monthsDecreaseSignificant treatment × time interaction. BMI: NS
47Overweight flexibility/strength exercise with or without β-blocker treatmentFlexibility/strength exercise for 45 min on 3 times/weekNone10 monthsNSBMI: NS

   
   
   
   
   
   
   
   
   
   
   
   
   
   
Nicklas et al. [63]
Base line: 70
6 months: 63:
18 months: 60
Overweight or obese older controlNoneNone18 months4.7 ± 3.2Changes
0.19 ± 2.8
(6 months)
0.27 ± 2.8
(18 months)
NSBM: NS
Base line: 67
6 months: 58:
18 months: 53
Overweight or obese exerciseExercise program consisted of an aerobic phase (15 min), a resistance-training phase (15 min), a second aerobic phase (15 min), and a cool-down phase (15 min) on 3 times/week.None18 months4.4 ± 3.1Changes
0.15 ± 1.8
(6 months)
0.02 ± 2.4
(18 months)
NSBM: NS
Base line: 71
6 months: 63:
18 months: 53
Overweight or obese dietary WLNoneCounseling to decrease their energy intake by 500 kcal/day18 months4.7 ± 3.4Changes
−0.51 ± 2.1
(6 months)
−0.71 ± 2.4
(18 months)
Main effect of WL, BM: decrease
Base line: 64
6 months: 58
18 months: 53
Overweight or obese exercise + dietary WLExercise program consisted of an aerobic phase (15 min), a resistance-training phase (15 min), a second aerobic phase (15 min), and a cool-down phase (15 min) on 3 times/week.Same as above18 months4.9 ± 3.0Changes
−0.35 ± 2.15
(6 months)
−0.35 ± 1.8
(18 months)
Main effect of WL, BM: decrease

Results are reported as mean ± SD or SE; P value reported for pre- versus post values. f: female; HRM: heart rate maximum; m: male; NS: not significant; WL: weight loss.

4. The Relationship between TR-Induced Changes in Adipokine Expression and WAT Mass

The size of WAT (adipocytes) greatly affects the expression of adipokines. As for leptin, mRNA expression and secretion are positively correlated with the size of adipocytes isolated from rodents and humans [31, 8284]. Similarly, in isolated adipocytes of humans, secretion of TNF-α, MCP-1, and IL-6 is positively correlated with cell size, and after correction for the cell surface, there is still a significant difference between very large and small adipocytes for MCP-1 and IL-6 [83]. Nevertheless, mRNA levels for TNF-α show no significant correlation with mouse adipocyte volume [84]. On the other hand, although the expression of adiponectin is reduced in the WAT of genetically obese mice and obese humans, the mRNA expression and secretion of adiponectin is positively correlated with isolated adipocyte size in rats and humans [31, 75, 76, 83]. One of the reasons for this discrepancy is speculated that reduced adiponectin expression in vivo may be the result of inflammatory adipokines, such as TNF-α, rather than increases in the size of adipocytes [58]. It is well known that TR reduces WAT mass, and, therefore, the reduction of WAT is thought to be a major factor in the effects of TR on adipokine expression in WAT (Figure 3). However, further research is needed regarding other effects of TR. Recently, an interesting study has examined the relationship between TR-induced changes in adipokine expression and WAT mass. Christiansen et al. [32] divided obese subjects into a group that underwent 12 weeks of combined aerobic exercise and diet therapy and a group that underwent diet therapy only, and after adjusting weight loss to approximate amounts, found no difference in changes in either the expression of inflammatory-related adipokines in subcutaneous WAT or in the circulating markers of inflammation; that is, TR seemed to have had no weight-independent effects in that study. On the other hand, when the authors observed a reduced level of leptin mRNA and an elevated mRNA level of adiponectin in rat visceral adipocytes after nine weeks of treadmill running, it suggested that the decrease in leptin mRNA expression depended on a reduction in adipocyte size, and that the increase in adiponectin mRNA was mediated by factor(s) other than adipocyte size [31]. In addition, Oberbach et al. [66] found that actual increases in blood adiponectin after TR were of a higher magnitude than increases in blood adiponectin levels that were predicted according to a regression line drawn from the negative correlation between body fat and the blood concentration of adiponectin.

During exercise, the secretion of catecholamines from the adrenal medulla and sympathetic nerve peripheries breaks down triglycerides within the adipocytes [12]. Several reports have indicated that β-adrenoceptor agonists affect the expression of some adipokines, such as TNF-α and adiponectin in WAT. Administration of β-adrenoceptor agonists in lean mice results in upregulation of TNF-α and downregulation of adiponectin in epididymal WAT [85, 86]. These findings seem to conflict with the beneficial effects of exercise on the disturbance of adipokines. Nevertheless, during exercise, since energy consumption is enhanced, the blockage of lipogenesis by the impaired insulin signaling in WAT might play reasonable roles in the proper execution of exercise. In contrast to lean mice, β-adrenoceptor agonists recovered the declined mRNA expression of adiponectin and suppressed the overexpressed mRNA level of TNF-α in WAT of KKAy mice [87]. Therefore, in obese and type 2 diabetic patients, it is likely that the secretion of catecholamines during exercise is one of the reasons for the attenuation of dysregulated adipokine expression in WAT (Figure 3).

Various possible mechanisms besides decreased WAT mass and secretion of catecholamines have been proposed, including decreased oxidative stress and improvement of hypoxia in WAT (Figure 3). Adipocytes have produced reactive oxygen, and obesity-induced increases in oxidative stress in WAT may be a cause of the dysregulated expression of inflammatory-related adipokines [88]. Studies have shown significantly lower levels of lipid peroxidation in WAT around the epididymis and retroperitoneum of rats that had undergone TR compared with a control group, and elevated protein levels of the antioxidant enzyme manganese superoxide dismutase (Mn-SOD) in the epididymal WAT of TR group rats [27, 28]. In that study, not only were protein levels of TNF-α and MCP-1 significantly lower in the epididymal WAT of the TR group, compared with those of the control group, the phosphorylation of extracellular signal-regulated kinase, which is activated by reactive oxygen and is important for the expression of MCP-1, also was reduced by TR in WAT around the epididymis and retroperitoneum [27, 89]. TR reduced WAT mass, which likely contributed to decreased oxidative stress in WAT. Nevertheless, because acute exercise elevates oxidative stress in the body [90], the adaptation of WAT against exposure to oxidative stress from exercise, in other words, the expansion of antioxidant systems via increases in Mn-SOD, could be one reason for decreased levels of proinflammatory adipokines.

Recent evidence that tissue hypoxia is involved in obesity-induced inflammatory changes in WAT has attracted the attention of researchers. In fact, oxygen partial pressure is lower in the WAT of obese animals and humans compared with controls, and results show that this may be related to the inflammatory response in WAT [91, 92]. Although some studies have focused on the impact of TR on blood flow in WAT, results from those studies appear to indicate that when WAT mass decreases due to TR, blood flow in the tissue increases [93]. We found that expression of mRNA for vascular endothelial growth factor and its receptor was elevated in the WAT stromal vascular fraction cells of rats that had engaged in TR, and that the vascular endothelial cell count per unit area had increased [94]. Thus, the increased blood flow to WAT produced by TR eliminated the obesity-induced hypoxia in WAT and could possibly have led to a weakening of the inflammatory changes in WAT.

5. Can TR That Does Not Alter Body and WAT Mass Alleviate Dysregulated Expression of Adipokines?

In many of the previous studies that examined the effects of TR on adipokine expression in WAT and on the blood levels of adipokines in human subjects, body mass, BMI, or WAT mass reduction is observed (Tables 15). For this reason, it remains unknown whether or not low-intensity TR that does not entail such reduction alters adipokine expression in WAT or blood adipokine levels. As described in the previous chapter, adipokine expression is affected by the size of the WAT (adipocyte). Among adipokines, expression of leptin seems to be especially largely affected by adipocyte size [8284]. In studies that examined the effect of TR on the blood leptin level in human subjects, results indicated that, in many cases, blood leptin levels do not change without a reduction in body fat; that is, decreased blood leptin levels are thought to be caused by exercise-induced WAT mass reduction (Table 2) [34, 36, 4145, 47]. In contrast, some studies have reported that the reduced blood leptin level shows beneficial effects of TR without WAT mass reduction. For example, studies on adult males and females have shown that only the female subjects exhibit reduced blood leptin levels without body fat loss after undergoing 12 weeks of TR [40]. Similarly, Ishii et al. [37] have demonstrated that TR in type 2 diabetic subjects reduces serum leptin levels independent of changes in body fat mass. On the other hand, increased blood adiponectin level through TR is also accompanied by reductions in body mass, BMI, or WAT mass (Table 4) [33, 45, 48, 65, 66]. Although Hsieh and Wang [48] observed that the blood adiponectin level was significantly elevated in type 2 diabetes patients who performed low-intensity TR (20 min/day, 50–74% maximum heart rate) and adequate calorie restriction for one year, this particular study showed that body mass reduction seemed to be beneficial for increases in adiponetin. However, other reports indicate that blood adiponectin levels do not change if body mass is decreased [38, 42, 67]. Thus, it is difficult to conclude at this stage whether loss of body and/or WAT mass is indispensable for adiponectin elevation. Moreover, the effects on TR-induced body and WAT mass reduction may differ depending on the type of adipokine. Taken together, these results show that although further examination is necessary, it is conceivable that changes in adipokine expression in WAT and blood adipokine level require TR that is sufficiently intense to reduce body mass or more specifically WAT mass.

6. Changes in Skeletal Muscle through TR and Its Impact on Expression of Adipokines in WAT

Skeletal muscle is responsible for physical exercise, and it is the largest tissue in the body. Undernutrition, aging, and sickness cause a decline in skeletal muscle mass (a condition known as muscular atrophy), deteriorating one’s exercise capacity [95, 96]. Moreover, skeletal muscle has a substantial impact on the overall metabolism of the body. For instance, skeletal muscles in patients with obesity and type 2 diabetes have reduced glucose metabolic capacity due to insulin resistance [97], and these observations are considered to be associated with the patients’ clinical conditions. Many studies have shown that TR can increase mitochondrial proliferation and boost the expression of a glucose transporter 4 (GLUT4), and can in turn enhance lipid and glucose metabolic capacities [98100]. Among the molecules involved in exercise-induced enhancement of glucose/lipid metabolic capacity in skeletal muscle, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) have been gaining a great deal of attention.

AMPK is an enzyme that is activated when ATP is converted to AMP and is a sensor of energy status that maintains cellular energy homeostasis [101, 102]. Skeletal muscle AMPK is activated by muscle contraction [103], treadmill running [104], and stimulation by its agonist aminoimidazole carboxamide ribonucleotide (AICAR) [105]. Upon activation, AMPK induces the phosphorylation of downstream effectors to elevate glucose uptake. Glucose uptake elevation has been associated with the induction of GLUT4 translocation to the cell membrane [106108]. AMPK activity has also been reported to be involved in fatty acid uptake through the fatty acid translocase FAT/CD36 and fatty acid oxidation mediated by reduced acetyl-CoA carboxylase enzymatic activity [103, 109]. TR has been shown to enhance both expression and activation of AMPK in skeletal muscle, and chronic AMPK activation in skeletal muscle can increase the number of mitochondria even in the absence of TR, suggesting that TR-induced AMPK activation is strongly involved in the increase in the mitochondria of skeletal muscle [110, 111]. However, a conclusion is yet to be drawn because AMPK KO mice that underwent TR also showed increases in skeletal muscle mitochondria [112].

Transcription coactivator PGC-1α forms a complex with nuclear receptors and transcription factors to regulate gene transcriptions, or more specifically, expression of genes involved in mitochondrial biosynthesis [113115]. In fact, mice with PGC-1α overexpression showed (1) increased number of mitochondria, (2) enhanced expressions of oxidizing enzymes such as cytochrome oxidase in skeletal muscle, and (3) transition to type I muscle fibers [114, 115]. Physical exercise increases PGC-1α transcription and potentially PGC-1α activity through posttranslational modifications, and concomitant PGC-1α-mediated gene regulation is suggested to be an underlying mechanism for adaptations in skeletal muscle, when exercise is repeated [115].

Muscle consumes the most energy out of all tissues in the body. Therefore, increases in mitochondria and increased insulin sensitivity in skeletal muscle by endurance TR are thought to dramatically impact the energy consumption of the whole body. Moreover, enhanced glucose/lipid metabolism in skeletal muscle is considered to be indirectly involved in WAT reduction, which results in altered adipokine expression (Figure 3). Additionally, because resting metabolic rate (RMR), which is the largest component of the daily energy budget in most human societies, is reportedly elevated owing to both aerobic and resistance training in human subjects, although some studies have failed to find such an effect [116], enhanced RMR is likely to cause alteration of adipokine expression following WAT mass reduction due to increased energy expenditure in the resting state (Figure 3). Nevertheless, the detailed mechanisms and whether mediators, such as myokines, from skeletal muscle act on the existence of WAT remain unknown. On the other hand, it is interesting that evidence is mounting on the new effects of adipokine on skeletal muscle metabolic capacity. Recent observation of KO mice showed that a lack of adiponectin receptor in their skeletal muscle showed a reduced mitochondrial content, reduced type I muscle fibers, and decreased capacity for exercise, suggesting that adiponectin is involved in mitochondrial biogenesis in skeletal muscles [117]. Furthermore, there is a significant positive correlation between blood adiponectin level and AMPK activity in the lateral great muscles in men [118]. In the future, it is crucial to examine the effect of TR on adipokine expression not only in WAT alone but also in terms of cross-talk between WAT and other tissues involving skeletal muscle. Further investigations are warranted.

7. Conclusions

Although reports on the effects of exercise on adipokine levels in WAT and blood may not always agree due to differences in experimental subjects, exercise intensity, or exercise duration, it is reasonable to believe that there is at least a positive effect. Although TR-induced WAT reduction is one of the key reasons for attenuation of dysregulated expression of adipokines, detailed studies about not only WAT-reducing effects of TR but also other effects, such as antioxidative effects and angiogenic effects, will be necessary to show the usefulness and distinctiveness of TR. Furthermore, it may be significantly beneficial to examine the cross-talk between WAT and other tissues involving skeletal muscle and to what degree WAT contributes to TR-induced changes in blood adipokine levels. Because the importance of exercise as a tool for preventing and improving obesity and lifestyle-related diseases can be expected to grow in the future, further research is desirable.

Conflict of Interests

The authors have no conflict of interests.

Acknowledgments

This work was partially supported by Grants-in-Aid for Specific Project Research from the Ministry of Education, Culture, Sport, Science, and Technology of Japan. The authors are also grateful for financial support from the Nakatomi Foundation, Tokyo, Japan.

References

  1. A. M. Prentice, “The emerging epidemic of obesity in developing countries,” International Journal of Epidemiology, vol. 35, no. 1, pp. 93–99, 2006. View at: Publisher Site | Google Scholar
  2. F. Sassi, Obesity and the Economics of Prevention: Fit Not Fat, OECD Publishing, Paris, France, 2010.
  3. M. Cecchini, F. Sassi, J. A. Lauer, Y. Y. Lee, V. Guajardo-Barron, and D. Chisholm, “Tackling of unhealthy diets, physical inactivity, and obesity: health effects and cost-effectiveness,” The Lancet, vol. 376, no. 9754, pp. 1775–1784, 2010. View at: Publisher Site | Google Scholar
  4. S. S. Bassuk and J. E. Manson, “Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease,” Journal of Applied Physiology, vol. 99, no. 3, pp. 1193–1204, 2005. View at: Publisher Site | Google Scholar
  5. M. J. Lamonte, S. N. Blair, and T. S. Church, “Physical activity and diabetes prevention,” Journal of Applied Physiology, vol. 99, no. 3, pp. 1205–1213, 2005. View at: Publisher Site | Google Scholar
  6. S. P. Helmrich, D. R. Ragland, R. W. Leung, and R. S. Paffenbarger Jr., “Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 325, no. 3, pp. 147–152, 1991. View at: Google Scholar
  7. J. E. Manson, D. M. Nathan, A. S. Krolewski, M. J. Stampfer, W. C. Willett, and C. H. Hennekens, “A prospective study of exercise and incidence of diabetes among US male physicians,” The Journal of the American Medical Association, vol. 268, no. 1, pp. 63–67, 1992. View at: Publisher Site | Google Scholar
  8. J. E. Manson, E. B. Rimm, M. J. Stampfer et al., “Physical activity and incidence of non-insulin-dependent diabetes mellitus in women,” The Lancet, vol. 338, no. 8770, pp. 774–778, 1991. View at: Publisher Site | Google Scholar
  9. H. Tilg and A. R. Moschen, “Adipocytokines: mediators linking adipose tissue, inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 10, pp. 772–783, 2006. View at: Publisher Site | Google Scholar
  10. K. Rabe, M. Lehrke, K. G. Parhofer, and U. C. Broedl, “Adipokines and insulin resistance,” Molecular Medicine, vol. 14, no. 11-12, pp. 741–751, 2008. View at: Publisher Site | Google Scholar
  11. C. N. Lumeng and A. R. Saltiel, “Inflammatory links between obesity and metabolic disease,” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2111–2117, 2011. View at: Publisher Site | Google Scholar
  12. J. F. Horowitz, “Fatty acid mobilization from adipose tissue during exercise,” Trends in Endocrinology and Metabolism, vol. 14, no. 8, pp. 386–392, 2003. View at: Publisher Site | Google Scholar
  13. Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, and J. M. Friedman, “Positional cloning of the mouse obese gene and its human homologue,” Nature, vol. 372, no. 6505, pp. 425–432, 1994. View at: Publisher Site | Google Scholar
  14. S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante Jr., “Obesity is associated with macrophage accumulation in adipose tissue,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003. View at: Publisher Site | Google Scholar
  15. H. Xu, G. T. Barnes, Q. Yang et al., “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1821–1830, 2003. View at: Publisher Site | Google Scholar
  16. G. Fantuzzi, “Adipose tissue, adipokines, and inflammation,” Journal of Allergy and Clinical Immunology, vol. 115, no. 5, pp. 911–919, 2005. View at: Publisher Site | Google Scholar
  17. J. L. Halaas, K. S. Gajiwala, M. Maffei et al., “Weight-reducing effects of the plasma protein encoded by the obese gene,” Science, vol. 269, no. 5223, pp. 543–546, 1995. View at: Google Scholar
  18. D. L. Morris and L. Rui, “Recent advances in understanding leptin signaling and leptin resistance,” American Journal of Physiology: Endocrinology and Metabolism, vol. 297, no. 6, pp. E1247–E1259, 2009. View at: Publisher Site | Google Scholar
  19. A. Oswal and G. Yeo, “Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity,” Obesity, vol. 18, no. 2, pp. 221–229, 2010. View at: Publisher Site | Google Scholar
  20. R. V. Considine, M. K. Sinha, M. L. Heiman et al., “Serum immunoreactive-leptin concentrations in normal-weight and obese humans,” The New England Journal of Medicine, vol. 334, no. 5, pp. 292–295, 1996. View at: Publisher Site | Google Scholar
  21. F. Lönnqvist, P. Arner, L. Nordfors, and M. Schalling, “Overexpression of the obese (ob) gene in adipose tissue of human obese subjects,” Nature Medicine, vol. 1, no. 9, pp. 950–953, 1995. View at: Google Scholar
  22. M. Mapfei, J. Halaas, E. Ravussin et al., “Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects,” Nature Medicine, vol. 1, no. 11, pp. 1155–1161, 1995. View at: Google Scholar
  23. J. J. Zachwieja, S. L. Hendry, S. R. Smith, and R. B. S. Harris, “Voluntary wheel running decreases adipose tissue mass and expression of leptin inRNA in Osborne-Mendel rats,” Diabetes, vol. 46, no. 7, pp. 1159–1166, 1997. View at: Google Scholar
  24. K. S. C. Gollisch, J. Brandauer, N. Jessen et al., “Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats,” American Journal of Physiology: Endocrinology and Metabolism, vol. 297, no. 7, pp. E495–E504, 2009. View at: Publisher Site | Google Scholar
  25. R. L. Bradley, J. Y. Jeon, F.-F. Liu, and E. Maratos-Flier, “Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice,” American Journal of Physiology: Endocrinology and Metabolism, vol. 295, no. 3, pp. E586–E594, 2008. View at: Publisher Site | Google Scholar
  26. V. J. Vieira, R. J. Valentine, K. R. Wilund, N. Antao, T. Baynard, and J. A. Woods, “Effects of exercise and low-fat diet on adipose tissue inflammation and metabolic complications in obese mice,” American Journal of Physiology: Endocrinology and Metabolism, vol. 296, no. 5, pp. E1164–E1171, 2009. View at: Publisher Site | Google Scholar
  27. T. Sakurai, T. Izawa, T. Kizaki et al., “Exercise training decreases expression of inflammation-related adipokines through reduction of oxidative stress in rat white adipose tissue,” Biochemical and Biophysical Research Communications, vol. 379, no. 2, pp. 605–609, 2009. View at: Publisher Site | Google Scholar
  28. T. Sakurai, M. Takei, J. Ogasawara et al., “Exercise training enhances tumor necrosis factor-α-induced expressions of anti-apoptotic genes without alterations in caspase-3 activity in rat epididymal adipocytes,” Japanese Journal of Physiology, vol. 55, no. 3, pp. 181–189, 2005. View at: Publisher Site | Google Scholar
  29. F. S. Lira, J. C. Rosa, A. S. Yamashita, C. H. Koyama, M. L. Batista Jr., and M. Seelaender, “Endurance training induces depot-specific changes in IL-10/TNF-α ratio in rat adipose tissue,” Cytokine, vol. 45, no. 2, pp. 80–85, 2009. View at: Publisher Site | Google Scholar
  30. M. Nara, T. Kanda, S. Tsukui et al., “Running exercise increases tumor necrosis factor-α secreting from mesenteric fat in insulin-resistant rats,” Life Sciences, vol. 65, no. 3, pp. 237–244, 1999. View at: Publisher Site | Google Scholar
  31. S. Miyazaki, T. Izawa, J.-E. Ogasawara et al., “Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectin,” Life Sciences, vol. 86, no. 17-18, pp. 691–698, 2010. View at: Publisher Site | Google Scholar
  32. T. Christiansen, S. K. Paulsen, J. M. Bruun, S. B. Pedersen, and B. Richelsen, “Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: a 12-week randomized intervention study,” American Journal of Physiology: Endocrinology and Metabolism, vol. 298, no. 4, pp. E824–E831, 2010. View at: Publisher Site | Google Scholar
  33. J. M. Bruun, J. W. Helge, B. Richelsen, and B. Stallknecht, “Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects,” American Journal of Physiology: Endocrinology and Metabolism, vol. 290, no. 5, pp. E961–E967, 2006. View at: Publisher Site | Google Scholar
  34. J. R. Berggren, M. W. Hulver, and J. A. Houmard, “Fat as an endocrine organ: influence of exercise,” Journal of Applied Physiology, vol. 99, no. 2, pp. 757–764, 2005. View at: Publisher Site | Google Scholar
  35. J. A. Houmard, J. H. Cox, P. S. MacLean, and H. A. Barakat, “Effect of short-term exercise training on leptin and insulin action,” Metabolism, vol. 49, no. 7, pp. 858–861, 2000. View at: Publisher Site | Google Scholar
  36. M. Halle, A. Berg, U. Garwers, D. Grathwohl, W. Knisel, and J. Keul, “Concurrent reductions of serum leptin and lipids during weight loss in obese men with type II diabetes,” American Journal of Physiology: Endocrinology and Metabolism, vol. 277, no. 2, pp. E277–E282, 1999. View at: Google Scholar
  37. T. Ishii, T. Yamakita, K. Yamagami et al., “Effect of exercise training on serum leptin levels in type 2 diabetic patients,” Metabolism, vol. 50, no. 10, pp. 1136–1140, 2001. View at: Publisher Site | Google Scholar
  38. P. Boudou, E. Sobngwi, F. Mauvais-Jarvis, P. Vexiau, and J.-F. Gautier, “Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men,” European Journal of Endocrinology, vol. 149, no. 5, pp. 421–424, 2003. View at: Publisher Site | Google Scholar
  39. R. R. Kraemer, G. R. Kraemer, E. O. Acevedo et al., “Effects of aerobic exercise an serum leptin levels in obese women,” European Journal of Applied Physiology and Occupational Physiology, vol. 80, no. 2, pp. 154–158, 1999. View at: Publisher Site | Google Scholar
  40. M. S. Hickey, J. A. Houmard, R. V. Considine et al., “Gender-dependent effects of exercise training on serum leptin levels in humans,” American Journal of Physiology: Endocrinology and Metabolism, vol. 272, no. 4, pp. E562–E566, 1997. View at: Google Scholar
  41. O. Ozcelik, H. Celik, A. Ayar, S. Serhatlioglu, and H. Kelestimur, “Investigation of the influence of training status on the relationship between the acute exercise and serum leptin levels in obese females,” Neuroendocrinology Letters, vol. 25, no. 5, pp. 381–385, 2004. View at: Google Scholar
  42. J. Polak, E. Klimcakova, C. Moro et al., “Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor α in obese women,” Metabolism, vol. 55, no. 10, pp. 1375–1381, 2006. View at: Publisher Site | Google Scholar
  43. T. Okazaki, E. Himeno, H. Nanri, H. Ogata, and M. Ikeda, “Effects of mild aerobic exercise and a mild hypocaloric diet on plasma leptin in sedentary women,” Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 5-6, pp. 415–420, 1999. View at: Publisher Site | Google Scholar
  44. L. Pérusse, G. Collier, J. Gagnon et al., “Acute and chronic effects of exercise on leptin levels in humans,” Journal of Applied Physiology, vol. 83, no. 1, pp. 5–10, 1997. View at: Google Scholar
  45. T. Kondo, I. Kobayashi, and M. Murakami, “Effect of exercise on circulating adipokine levels in obese young women,” Endocrine Journal, vol. 53, no. 2, pp. 189–195, 2006. View at: Publisher Site | Google Scholar
  46. J. E. Reseland, S. A. Anderssen, K. Solvoll et al., “Effect of long-term changes in diet and exercise on plasma leptin concentrations,” American Journal of Clinical Nutrition, vol. 73, no. 2, pp. 240–245, 2001. View at: Google Scholar
  47. N. Miyatake, K. Takahashi, J. Wada et al., “Changes in serum leptin concentrations in overweight Japanese men after exercise,” Diabetes, Obesity and Metabolism, vol. 6, no. 5, pp. 332–337, 2004. View at: Publisher Site | Google Scholar
  48. C. J. Hsieh and P. W. Wang, “Effectiveness of weight loss in the elderly with type 2 diabetes mellitus,” Journal of Endocrinological Investigation, vol. 28, no. 11, pp. 973–977, 2005. View at: Google Scholar
  49. A. S. Ryan, R. E. Pratley, D. Elahi, and A. P. Goldberg, “Changes in plasma leptin and insulin action with resistive training in postmenopausal women,” International Journal of Obesity, vol. 24, no. 1, pp. 27–32, 2000. View at: Publisher Site | Google Scholar
  50. I. G. Fatouros, S. Tournis, D. Leontsini et al., “Leptin and adiponectin responses in overweight inactive elderly following resistance training and detraining are intensity related,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 5970–5977, 2005. View at: Publisher Site | Google Scholar
  51. C. Qi and P. H. Pekala, “Tumor necrosis factor-α-induced insulin resistance in adipocytes,” Proceedings of the Society for Experimental Biology and Medicine, vol. 223, no. 2, pp. 128–135, 2000. View at: Google Scholar
  52. W. P. Cawthorn and J. K. Sethi, “TNF-α and adipocyte biology,” FEBS Letters, vol. 582, no. 1, pp. 117–131, 2008. View at: Publisher Site | Google Scholar
  53. G. S. Hotamisligil, P. Arner, J. F. Caro, R. L. Atkinson, and B. M. Spiegelman, “Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance,” The Journal of Clinical Investigation, vol. 95, no. 5, pp. 2409–2415, 1995. View at: Google Scholar
  54. G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993. View at: Google Scholar
  55. P. A. Kern, M. Saghizadeh, J. M. Ong, R. J. Bosch, R. Deem, and R. B. Simsolo, “The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase,” The Journal of Clinical Investigation, vol. 95, no. 5, pp. 2111–2119, 1995. View at: Google Scholar
  56. G. S. Hotamisligil, A. Budavari, D. Murray, and B. M. Spiegelman, “Reduced tyrosine kinase activity of the insulin receptor in obesity- diabetes. Central role of tumor necrosis factor-α,” The Journal of Clinical Investigation, vol. 94, no. 4, pp. 1543–1549, 1994. View at: Google Scholar
  57. G. S. Hotamisligil, D. L. Murray, L. N. Choy, and B. M. Spiegelman, “Tumor necrosis factor α inhibits signaling from the insulin receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4854–4858, 1994. View at: Publisher Site | Google Scholar
  58. N. Maeda, M. Takahashi, T. Funahashi et al., “PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein,” Diabetes, vol. 50, no. 9, pp. 2094–2099, 2001. View at: Google Scholar
  59. A. Katsuki, Y. Sumida, S. Murashima et al., “Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 3, pp. 859–862, 1998. View at: Publisher Site | Google Scholar
  60. M. Stŗczkowski, I. Kowalska, S. Dzienis-Stŗczkowska et al., “Changes in tumor necrosis factor-α system and insulin sensitivity during an exercise training program in obese women with normal and impaired flucose tolerance,” European Journal of Endocrinology, vol. 145, no. 3, pp. 273–280, 2001. View at: Google Scholar
  61. L. Horne, G. Bell, B. Fisher, S. Warren, and A. Janowska-Wieczorek, “Interaction between cortisol and tumour necrosis factor with concurrent resistance and endurance training,” Clinical Journal of Sport Medicine, vol. 7, no. 4, pp. 247–251, 1997. View at: Google Scholar
  62. M. L. Kohut, D. A. McCann, D. W. Russell et al., “Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of β-blockers, BMI, and psychosocial factors in older adults,” Brain, Behavior, and Immunity, vol. 20, no. 3, pp. 201–209, 2006. View at: Publisher Site | Google Scholar
  63. B. J. Nicklas, W. Ambrosius, S. P. Messier et al., “Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial,” American Journal of Clinical Nutrition, vol. 79, no. 4, pp. 544–551, 2004. View at: Google Scholar
  64. M. Trøseid, K. T. Lappegård, T. Claud et al., “Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome,” European Heart Journal, vol. 25, no. 4, pp. 349–355, 2004. View at: Google Scholar
  65. M. Blüher, J. W. Bullen Jr., J. H. Lee et al., “Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 6, pp. 2310–2316, 2006. View at: Publisher Site | Google Scholar
  66. A. Oberbach, A. Tönjes, N. Klöting et al., “Effect of a 4 week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance,” European Journal of Endocrinology, vol. 154, no. 4, pp. 577–585, 2006. View at: Google Scholar
  67. V. B. O'Leary, C. M. Marchetti, R. K. Krishnan, B. P. Stetzer, F. Gonzalez, and J. P. Kirwan, “Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat,” Journal of Applied Physiology, vol. 100, no. 5, pp. 1584–1589, 2006. View at: Publisher Site | Google Scholar
  68. G. P. Nassis, K. Papantakou, K. Skenderi et al., “Aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, adiponectin, and inflammatory markers in overweight and obese girls,” Metabolism, vol. 54, no. 11, pp. 1472–1479, 2005. View at: Publisher Site | Google Scholar
  69. M. W. Hulver, D. Zheng, C. J. Tanner et al., “Adiponectin is not altered with exercise training despite enhanced insulin action,” American Journal of Physiology: Endocrinology and Metabolism, vol. 283, no. 4, pp. E861–E865, 2002. View at: Google Scholar
  70. N. Kamei, K. Tobe, R. Suzuki et al., “Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance,” The Journal of Biological Chemistry, vol. 281, no. 36, pp. 26602–26614, 2006. View at: Publisher Site | Google Scholar
  71. H. Kanda, S. Tateya, Y. Tamori et al., “MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity,” The Journal of Clinical Investigation, vol. 116, no. 6, pp. 1494–1505, 2006. View at: Publisher Site | Google Scholar
  72. T. Kadowaki, T. Yamauchi, N. Kubota, K. Hara, K. Ueki, and K. Tobe, “Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome,” The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1784–1792, 2006. View at: Publisher Site | Google Scholar
  73. T. Kadowaki and T. Yamauchi, “Adiponectin and adiponectin receptors,” Endocrine Reviews, vol. 26, no. 3, pp. 439–451, 2005. View at: Publisher Site | Google Scholar
  74. A. M. Wolf, D. Wolf, H. Rumpold, B. Enrich, and H. Tilg, “Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes,” Biochemical and Biophysical Research Communications, vol. 323, no. 2, pp. 630–635, 2004. View at: Publisher Site | Google Scholar
  75. E. Hu, P. Liang, and B. M. Spiegelman, “AdipoQ is a novel adipose-specific gene dysregulated in obesity,” The Journal of Biological Chemistry, vol. 271, no. 18, pp. 10697–10703, 1996. View at: Publisher Site | Google Scholar
  76. Y. Arita, S. Kihara, N. Ouchi et al., “Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity,” Biochemical and Biophysical Research Communications, vol. 257, no. 1, pp. 79–83, 1999. View at: Publisher Site | Google Scholar
  77. T. Kishimoto, “Interleukin-6: from basic science to medicine—40 years in immunology,” Annual Review of Immunology, vol. 23, pp. 1–21, 2005. View at: Publisher Site | Google Scholar
  78. A. M. W. Petersen and B. K. Pedersen, “The anti-inflammatory effect of exercise,” Journal of Applied Physiology, vol. 98, no. 4, pp. 1154–1162, 2005. View at: Publisher Site | Google Scholar
  79. J. R. Berggren, M. W. Hulver, and J. A. Houmard, “Fat as an endocrine organ: influence of exercise,” Journal of Applied Physiology, vol. 99, no. 2, pp. 757–764, 2005. View at: Publisher Site | Google Scholar
  80. K. Eder, N. Baffy, A. Falus, and A. K. Fulop, “The major inflammatory mediator interleukin-6 and obesity,” Inflammation Research, vol. 58, no. 11, pp. 727–736, 2009. View at: Publisher Site | Google Scholar
  81. C. P. Fischer, “Interleukin-6 in acute exercise and training: what is the biological relevance?” Exercise Immunology Review, vol. 12, pp. 6–33, 2006. View at: Google Scholar
  82. K.-Y. Guo, P. Halo, R. L. Leibel, and Y. Zhang, “Effects of obesity on the relationship of leptin mRNA expression and adipocyte size in anatomically distinct fat depots in mice,” American Journal of Physiology: Regulatory Integrative and Comparative Physiology, vol. 287, no. 1, pp. R112–R119, 2004. View at: Publisher Site | Google Scholar
  83. T. Skurk, C. Alberti-Huber, C. Herder, and H. Hauner, “Relationship between adipocyte size and adipokine expression and secretion,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 3, pp. 1023–1033, 2007. View at: Publisher Site | Google Scholar
  84. Y. Zhang, K.-Y. Guo, P. A. Diaz, M. Heo, and R. L. Leibel, “Determinants of leptin gene expression in fat depots of lean mice,” American Journal of Physiology: Regulatory Integrative and Comparative Physiology, vol. 282, no. 1, pp. R226–R234, 2002. View at: Google Scholar
  85. M.-L. Delporte, T. Funahashi, M. Takahashi, Y. Matsuzawa, and S. M. Brichard, “Pre- and post-translational negative effect of β-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies,” Biochemical Journal, vol. 367, no. 3, pp. 677–685, 2002. View at: Publisher Site | Google Scholar
  86. L. Fu, K. Isobe, Q. Zeng, K. Suzukawa, K. Takekoshi, and Y. Kawakami, “β-adrenoceptor agonists downregulate adiponectin, but upregulate adiponectin receptor 2 and tumor necrosis factor-α expression in adipocytes,” European Journal of Pharmacology, vol. 569, no. 1-2, pp. 155–162, 2007. View at: Publisher Site | Google Scholar
  87. L. Fu, K. Isobe, Q. Zeng, K. Suzukawa, K. Takekoshi, and Y. Kawakami, “The effects of β3-adrenoceptor agonist CL-316,243 on adiponectin, adiponectin receptors and tumor necrosis factor-α expressions in adipose tissues of obese diabetic KKAy mice,” European Journal of Pharmacology, vol. 584, no. 1, pp. 202–206, 2008. View at: Publisher Site | Google Scholar
  88. S. Furukawa, T. Fujita, M. Shimabukuro et al., “Increased oxidative stress in obesity and its impact on metabolic syndrome,” The Journal of Clinical Investigation, vol. 114, no. 12, pp. 1752–1761, 2004. View at: Publisher Site | Google Scholar
  89. A. Ito, T. Suganami, Y. Miyamoto et al., “Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy,” The Journal of Biological Chemistry, vol. 282, no. 35, pp. 25445–25452, 2007. View at: Publisher Site | Google Scholar
  90. C. E. Cooper, N. B. Vollaard, T. Choueiri, and M. T. Wilson, “Exercise, free radicals and oxidative stress,” Biochemical Society Transactions, vol. 30, no. 2, pp. 280–285, 2002. View at: Google Scholar
  91. N. Hosogai, A. Fukuhara, K. Oshima et al., “Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation,” Diabetes, vol. 56, no. 4, pp. 901–911, 2007. View at: Publisher Site | Google Scholar
  92. J. Ye, Z. Gao, J. Yin, and Q. He, “Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice,” American Journal of Physiology: Endocrinology and Metabolism, vol. 293, no. 4, pp. E1118–E1128, 2007. View at: Publisher Site | Google Scholar
  93. B. Stallknecht, “Influence of physical training on adipose tissue metabolism—with special focus on effects of insulin and epinephrine,” Danish Medical Bulletin, vol. 51, no. 1, pp. 1–33, 2004. View at: Google Scholar
  94. D. Hatano, J. Ogasawara, S. Endoh et al., “Effect of exercise training on the density of endothelial cells in the white adipose tissue of rats,” Scandinavian Journal of Medicine and Science in Sports, vol. 21, no. 6, pp. e115–e121, 2011. View at: Publisher Site | Google Scholar
  95. K. L. English and D. Paddon-Jones, “Protecting muscle mass and function in older adults during bed rest,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 13, no. 1, pp. 34–39, 2010. View at: Publisher Site | Google Scholar
  96. B, T. Wall, and L. J. van Loon, “Nutritional strategies to attenuate muscle disuse atrophy,” Nutrition Reviews, vol. 71, no. 4, pp. 195–208, 2013. View at: Google Scholar
  97. V. T. Samuel and G. I. Shulman, “Mechanisms for insulin resistance: common threads and missing links,” Cell, vol. 148, no. 5, pp. 852–871, 2012. View at: Publisher Site | Google Scholar
  98. Z. Yan, M. Okutsu, Y. N. Akhtar, and V. A. Lira, “Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle,” Journal of Applied Physiology, vol. 110, no. 1, pp. 264–274, 2011. View at: Publisher Site | Google Scholar
  99. J. O. Holloszy, “Exercise-induced increase in muscle insulin sensitivity,” Journal of Applied Physiology, vol. 99, no. 1, pp. 338–343, 2005. View at: Publisher Site | Google Scholar
  100. E. O. Ojuka, V. Goyaram, and J. A. Smith, “The role of CaMKII in regulating GLUT4 expression in skeletal muscle,” American Journal of Physiology: Endocrinology and Metabolism, vol. 303, no. 3, pp. E322–E331, 2012. View at: Google Scholar
  101. D. G. Hardie, “AMP-activated protein kinase-an energy sensor that regulates all aspects of cell function,” Genes and Development, vol. 25, no. 18, pp. 1895–1908, 2011. View at: Publisher Site | Google Scholar
  102. D. G. Hardie, “AMPK: a key regulator of energy balance in the single cell and the whole organism,” International Journal of Obesity, vol. 32, no. 4, pp. S7–S12, 2008. View at: Publisher Site | Google Scholar
  103. D. Vavvas, A. Apazidis, A. K. Saha et al., “Contraction-induced changes in acetyl-CoA carboxylase and 5'-AMP- activated kinase in skeletal muscle,” The Journal of Biological Chemistry, vol. 272, no. 20, pp. 13255–13261, 1997. View at: Publisher Site | Google Scholar
  104. W. W. Winder and D. G. Hardie, “Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise,” American Journal of Physiology: Endocrinology and Metabolism, vol. 270, no. 2, pp. E299–E304, 1996. View at: Google Scholar
  105. G. F. Merrill, E. J. Kurth, D. G. Hardie, and W. W. Winder, “AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle,” American Journal of Physiology: Endocrinology and Metabolism, vol. 273, no. 6, pp. E1107–E1112, 1997. View at: Google Scholar
  106. T. Hayashi, M. F. Hirshman, E. J. Kurth, W. W. Winder, and L. J. Goodyear, “Evidence for 5'AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport,” Diabetes, vol. 47, no. 8, pp. 1369–1373, 1998. View at: Publisher Site | Google Scholar
  107. E. J. Kurth-Kraczek, M. F. Hirshman, L. J. Goodyear, and W. W. Winder, “5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle,” Diabetes, vol. 48, no. 8, pp. 1667–1671, 1999. View at: Publisher Site | Google Scholar
  108. H. M. O'Neill, “AMPK and exercise: glucose uptake and insulin sensitivity,” Diabetes & Metabolism Journal, vol. 37, no. 1, pp. 1–21, 2013. View at: Google Scholar
  109. A. Bonen, X.-X. Han, D. D. J. Habets, M. Febbraio, J. F. C. Glatz, and J. J. F. P. Luiken, “A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and AICAR-stimulated fatty acid metabolism,” American Journal of Physiology: Endocrinology and Metabolism, vol. 292, no. 6, pp. E1740–E1749, 2007. View at: Publisher Site | Google Scholar
  110. R. Bergeron, J. M. Ren, K. S. Cadman et al., “Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis,” American Journal of Physiology: Endocrinology and Metabolism, vol. 281, no. 6, pp. E1340–E1346, 2001. View at: Google Scholar
  111. W. W. Winder, B. F. Holmes, D. S. Rubink, E. B. Jensen, M. Chen, and J. O. Holloszy, “Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle,” Journal of Applied Physiology, vol. 88, no. 6, pp. 2219–2226, 2000. View at: Google Scholar
  112. S. B. Jørgensen, J. F. P. Wojtaszewski, B. Viollet et al., “Effects of α-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle,” FASEB Journal, vol. 19, no. 9, pp. 1146–1148, 2005. View at: Publisher Site | Google Scholar
  113. P. Puigserver and B. M. Spiegelman, “Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator,” Endocrine Reviews, vol. 24, no. 1, pp. 78–90, 2003. View at: Publisher Site | Google Scholar
  114. H. Liang and W. F. Ward, “PGC-1α: a key regulator of energy metabolism,” American Journal of Physiology: Advances in Physiology Education, vol. 30, no. 4, pp. 145–151, 2006. View at: Publisher Site | Google Scholar
  115. J. Olesen, K. Kiilerich, and H. Pilegaard, “PGC-1α-mediated adaptations in skeletal muscle,” Pflügers Archiv, vol. 460, no. 1, pp. 153–162, 2010. View at: Publisher Site | Google Scholar
  116. J. R. Speakman and C. Selman, “Physical activity and resting metabolic rate,” Proceedings of the Nutrition Society, vol. 62, no. 3, pp. 621–634, 2003. View at: Publisher Site | Google Scholar
  117. M. Iwabu, T. Yamauchi, M. Okada-Iwabu et al., “Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1,” Nature, vol. 464, no. 7293, pp. 1313–1319, 2010. View at: Publisher Site | Google Scholar
  118. L. D. Høeg, K. A. Sjøberg, A. M. Lundsgaard et al., “Adiponectin concentration is associated with muscle insulin sensitivity, AMPK phosphorylation, and ceramide content in skeletal muscles of men but not women,” Journal of Applied Physiology, vol. 114, no. 5, pp. 592–601, 2013. View at: Google Scholar

Copyright © 2013 Takuya Sakurai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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