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J Exerc Rehabil > Volume 10(2);2014 > Article
Lee and Kwak: Effects of interventions on adiponectin and adiponectin receptors

Abstract

Adiponectin secreted from adipose tissue binds to two distinct adiponectin receptors (AdipoR1 and AdipoR2) identified and exerts its anti-diabetic effects in insulin-sensitive organs including liver, skeletal muscle and adipose tissue as well as amelioration of vascular dysfunction in the various vasculatures. A number of experimental and clinical observations have demonstrated that circulating levels of adiponectin are markedly reduced in obesity, type 2 diabetes, hypertension, and coronary artery disease. Therapeutic interventions which can improve the action of adiponectin including elevation of circulating adiponectin concentration or up-regulation and/or activation of its receptors, could provide better understanding of strategies to ameliorate metabolic disorders and vascular disease. The focus of the present review is to summarize accumulating evidence showing the role of interventions such as pharmacological agents, exercise, and calorie restriction in the expression of adiponectin and adiponectin receptors.

INTRODUCTION

Nutrition imbalance and physical inactivity due to sedentary life style can lead to obesity, which is closely associated with an increased risk of metabolic syndrome (Booth et al., 2011; Booth et al., 2012). Metabolic disorders including insulin resistance and overt type 2 diabetes (T2D) are highly related to secondary cardiovascular complications such as hypertension, myocardial infarction, and stroke (Abate, 2000; Meshkani and Adeli, 2009). Adiponectin is one of adipokines secreted from adipose tissue and involved in various biological processes such as energy homeostasis, immune actions, and vascular homeostasis (Cheng et al., 2014; Hui et al., 2012). A number of clinical observations have demonstrated that circulating levels of adiponectin are markedly reduced in patients with obesity (Arita et al., 1999), T2D (Hotta et al., 2000), essential hypertension (Adamczak et al., 2003), and coronary artery disease (CAD) (Kumada et al., 2003; Nakamura et al., 2004). Based on above considerations, therapeutic interventions which can improve the action of adiponectin including elevation of circulating adiponectin concentration or up-regulation and/or activation of its receptors, could provide better understanding of strategies to ameliorate metabolic disorders and vascular disease. The focus of the present review is to summarize accumulating evidence showing the role of interventions such as pharmacological agents, exercise, calorie restriction (CR), and gastric bypass surgery (weight loss) in the expression of adiponectin and adiponectin receptors.

EFFECTS OF INTERVENTIONS ON ADIPONECTIN AND ADIPONECTIN RECEPTORS

Pharmacological/dietary interventions and lifestyle modifications such as exercise and CR to prevent and ameliorate cardiovascular disease and micro-vascular complications in T2D, have been shown to increase circulating levels of adiponectin in both experimental models and human studies (Simpson and Singh, 2008; Zhu et al., 2008). Up-regulation of endogenous adiponectin and its receptors by interventions might have multiple beneficial effects on metabolic and cardiovascular diseases.

Pharmacological and dietary intervention

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor superfamily which functions as transcription factors regulating gene expression and play important roles in the regulation of cellular differentiation, development, and energy metabolism (Schoonjans et al., 1996). The three types of PPAR (α, γ, and β/δ) have been identified (Schoonjans et al., 1996). The PPAR-γ agonists, thiazolidinediones (TZDs) are widely used for anti-diabetic drugs that improve insulin sensitivity through enhancement of glucose disposal as well as reduction of gluconeogenesis in the target tissues of the body including skeletal muscle, liver, and adipose tissue (Furnsinn and Waldhausl, 2002; Kintscher and Law, 2005). A number of studies have shown that TZDs such as rosiglitazone and pioglitazone increased circulating levels of adiponectin in both human and experimental rodent models (Choi et al., 2005; Iwaki et al., 2003; Kubota et al., 2006; Pajvani et al., 2004). In addition to PPAR-γ, the PPAR-α agonist induced the increase in the circulating level of adiponectin associated with improvement in insulin sensitivity. For example, fenofibrate an agonist of nuclear receptor PPAR-α, increased serum levels of adiponectin in patients with primary hypertriglyceridemia (Koh et al., 2005). Previous studies have implicated that hypoadiponectinemia is associated with hypertension (Adamczak et al., 2003; Papadopoulos et al., 2009). Therefore, it is tempting to speculate whether anti-hypertensive drugs such as candesartan and losartan (angiotensin II receptor antagonists) increase adiponectin. These drugs, indeed, elevated circulating adiponectin without altering adiposity (Celik et al., 2006; Furuhashi et al., 2003; Koh et al., 2004; Koh et al., 2006). In addition, several other drugs for anti-diabetic (glimepiride) and anti-hypertension (nebivolol, β1 receptor blocker) have been shown to enhance plasma adiponectin concentrations in human subjects (Celik et al., 2006; Nagasaka et al., 2003). However, it is unclear whether elevated adiponectin is associated with improved cardiovascular outcomes.
In addition to pharmacological agents, dietary fish oils (FO) and polyunsaturated fatty acids (PUFA) have been shown to increase mRNA expression of adiponectin in adipose tissue and circulating levels of adiponectin in several experimental models and human (Mostowik et al., 2013; Neschen et al., 2006; Rossi et al., 2005). Furthermore, Oolong tea, green tea extract and (-)-catechin increased plasma adiponectin in humans and rodent models (Cho et al., 2007; Li et al., 2006; Shimada et al., 2004). Table 1 summarized the effects of pharmacological agents and dietary intervention on the expression of adiponectin.

Exercise

It is well documented that exercise or regular physical activity has beneficial effects on metabolic and cardiovascular disease. Considering previous literatures, it is unclear whether exercise training (physical activity) increases adiponectin in circulation and its receptors in insulin-sensitive tissues such as adipose tissue, liver, and skeletal muscle. Complicating interpretation of the existing data is dependent on multiple factors including species, the pathological condition, types (endurance vs resistance exercise), intensity (low, moderate, and intense), and duration of exercise (acute vs chronic, short-term vs long-term), and sex. For example, in healthy, young subjects, it seemed that both acute and chronic aerobic exercise did not alter plasma level of adiponectin (Ferguson et al., 2004; Hulver et al., 2002; Jurimae et al., 2006; Punyadeera et al., 2005). However, chronic endurance training increased plasma adiponectin in obese adolescents (Balagopal et al., 2005), obese adults (Kondo et al., 2006), Caucasian subjects with impaired glucose tolerance (IGT) and T2D (Bluher et al., 2006; Oberbach et al., 2006). Furthermore, endurance training increased mRNA expression of adiponectin receptor (AdipoR) 1 and 2 in adipose tissue and skeletal muscle in normal glucose tolerance (NGT), IGT, and type 2 diabetic patients (Bluher et al., 2006; Bluher et al., 2007; Oberbach et al., 2006). On the other hand, some studies by several other groups have shown that aerobic exercise did not change adiponectin expression in obese subject (Polak et al., 2006), insulin resistant female subjects (Marcell et al., 2005), and patients with T2D (Boudou et al., 2003; Yokoyama et al., 2004). Interestingly, Fatouros et al. have demonstrated that only moderate-high intensity resistance training, not low intensity, increased plasma adiponectin in inactive subjects, suggesting that the intensity of exercise may be an important factor in the expression of adiponectin (Fatouros et al., 2005). Table 2 shows a summary of studies examining effects of exercise training on adiponectin and AdipoRs in both human and experimental models.

Calorie restriction, weight loss, and gastric bypass surgery

Calorie restriction (CR) refers to a dietary regimen low in calories without malnutrition and is known as an efficient lifestyle modification that delays the onset of metabolic and cardiovascular disease (Cava and Fontana, 2013). Weight loss and/or CR have been shown to improve insulin resistance, T2D, and cardiovascular dysfunction in both human and rodent models (Weiss and Fontana, 2011). In addition, sustained weight loss by gastric bypass surgery ameliorated cardiovascular dysfunction (Brethauer et al., 2011; Zhang et al., 2011). Although it is not clear whether beneficial effects of these interventions are mediated by adiponectin signaling pathways, a number of studies have shown that CR and/or weight loss by gastric bypass surgery increased circulating levels of adiponectin. For example, CR increased circulating adiponectin in normal (Fontana et al., 2010; Schulte et al., 2013) and obese subjects (Kobayashi et al., 2004; Oberhauser et al., 2012; Varady et al., 2010). However, some studies have shown that CR did not change plasma levels of adiponectin in patients with metabolic syndrome (Xydakis et al., 2004) and T2D (Plum et al., 2011). Interestingly, Varady et al. (2009) have implicated that circulating adiponectin concentration increased 20% in the 5–10% weight loss group, not less than 5% weight loss group, suggesting a minimum degree of weight loss are required to improve adipokine profile in severely obese women. On the other hand, Plum et al. suggested that Roux-en-Y gastric bypass surgery, not low calorie diet group, increased plasma adiponectin concentration in patients with T2D, although weight loss was comparable in both groups (Plum et al., 2011). This may suggest that Roux-en-Y gastric bypass surgery is more effective method than low calorie diet regimen in some kinds of obese diabetic patients. Because metabolic and cardiovascular diseases are multi-factorial phenomena, we need to consider the effect of other metabolic disorders such as dyslipidemia, hypercholesterolemia, and hypertension on the expression of adiponectin. Table 3 summarizes the effects of CR, weight loss and gastric bypass surgery on adiponectin.

CONCLUSIONS

There is no doubt that pharmacological agents and lifestyle modifications affect metabolic and cardiovascular disease. In regard to the expression of adiponectin and its receptors with these interventions, it remains unclear whether these interventions ameliorate metabolic and cardiovascular dysfunction through adiponectin and its receptors-mediated signaling pathways. Recent studies provide compelling evidence supporting the beneficial role of adiponectin in the metabolic and cardiovascular diseases. Although significant progress has made in understanding the molecular mechanisms that underlie the beneficial actions of adiponectin, it should be noted that large discrepancies exist among those studies based on experimental design including species, type of intervention, and the pathological condition. Further investigations in adiponectin signaling pathways will provide potential targets used for the therapeutic interventions in metabolic and cardiovascular disease.

Notes

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This work was supported by Inha University Research Grant.

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Table 1.
Effects of pharmacological agents and dietary intervention on adiponectin
Subject or animal Sex Pharmacological agents Duration Methods for intake Tissues Methods Conclusions References
Non-diabetic patients Female -Pioglitazone (1–3 μM) 24 h Cell culture Subcutaneous fat (Biopsy) PCR
WB
= APN ↑ HMW APN Bodles et al., 2006
Normal volunteers Male -Rosiglitazone (4 mg twice/daily) 2 wk Oral intake Serum sedimentation Velocity ↑ Total APN
↑ HMW APN
Pajvani et al., 2004
Healthy normal weight subjects Both -Flaxseed oil (15 mL/day)
-Olive oil (15 mL/day)
6 wk Oral intake Plasma ELISA = APN
= APN
Kontogianni et al., 2013
Patients with primary hypertriglyceridemia Both -Fenofibrate (200 mg daily) 8 wk Oral intake Serum ELISA ↑ APN Koh et al., 2005
Patients with hypercholes terolemic hypertension Both -Simvastatin (20 mg) +Losartan (100 mg)
-Losartan only (100 mg/daily)
2 mo Oral intake Plasma ELISA ↑ APN
↑ APN
Koh et al., 2004
Patients with essential hypertension Both -Temocapril (4 mg/daily)
-Candesartan (8 mg/daily)
2 wk Oral intake Serum ELISA ↑ APN
↑ APN
Furuhashi et al., 2003
Patients with mild to moderate hypertension Both -Candesartan (16 mg/daily) 2 mo Oral intake Plasma ELISA ↑ APN Koh et al., 2006
Patients with hypertension Both -Nebivolol (5 mg/daily)
-Metoprolol (100 mg/daily)
6 mo Oral intake Plasma ELISA ↑ APN
= APN
Celik et al., 2006
Patients with T2D Both -Glimepiride (1.9 mg/daily)
-Metformin (750 mg/daily)
3 mo Oral intake Serum ELISA ↑ APN
↑ APN
Nagasaka et al., 2003
Patients with CAD Both -Oolong tea (1,000 mL) vs. water 1 mo Oral intake Plasma ELISA ↑ APN Shimada et al., 2004
Patients with CAD Both -Omega-3 PUFA 4 wk Oral intake Plasma ELISA ↑ APN Mostowik et al., 2013
Rats (OLETF) Male -Rosiglitazone (2 mg/kg/day)
-Fenofibrate (100 mg/kg/day)
40 wk In food Serum ELISA ↑ APN
= APN
Choi et al., 2005
Rats (Wistar) Male -Sucrose Rich Diet
-Sucrose Rich Diet (7 mo)+FO Diet (2 mo)
9 mo In food Plasma ELISA ↓ APN
↑ APN
Rossi et al., 2005
Hamsters (Golden Syrian) Male -Green tea extract (low dose 150 mg/kg)
-Green tea extract (high dose 300 mg/kg)
4 wk Oral gavage Plasma ELISA ↑ APN
↑ APN
Li et al., 2006
Hamsters (Golden Syrian) Male -Niacin (1,200 mg/kg) 18 days Oral gavage AT PCR ↑ APN Connolly et al., 2013
Mice (ob/ob) Male -Pioglitazone (10 mg/kg)
-Pioglitazone (30 mg/kg)
2 wk Oral gavage Serum ELISA ↑ APN
↑↑ APN
Kubota et al., 2006
Mice (db/db) Male -Troglitazone (0.2%)
-Pioglitazone (0.01%)
2 wk In food Subcutaneous AT
Serum
PCR
WB
↑ APN
↑ APN
Iwaki et al., 2003
Mice (db/db) Male -Rosiglitazone (10 mg/kg) 11 days Oral gavage Serum sedimentation Velocity = Total APN
↑ HMW APN
Pajvani et al., 2004
Mice (129 Sv) Male −27% Fish oil 8 or 15 days In food Plasma
Epididymal AT
Subcutaneous AT
ELISA
PCR
PCR
↑ APN
↑ APN
= APN
Neschen et al., 2006
Mice (3T3-L1 adipocytes) - (-)-catechin (50 μM)
(-)-catechin (5–100 μM)
(-)-catechin (50 μM)
24 h Cell culture Adipocytes WB
ELISA
PCR
↑ APN
↑ APN
↑ APN
Cho et al., 2007

APN, adiponectin; AT, adipose tissue; CAD, coronary artery disease; db/db, leptin receptor mutated mouse; ELISA, enzyme linked immunosorbent assay; FO, fish oil; HMW, high molecular weight; OLETF rat, Otsuka Long-Evans Tokushima fatty rat; ob/ob, leptin deficient mouse; PCR, polymerase chain reaction; PUFA, polyunsaturated fatty acid; T2D, type 2 diabetes; WB, western blotting; ↑, increase; ↓, decrease; =, no change.

Table 2.
Effects of exercise on adiponectin and adiponectin receptors
Subject or animal Sex Type of exercise Duration Tissues Methods Conclusions References
Healthy subjects Both Cycle ergometry training 60 min (Acute) Plasma ELISA = APN Ferguson et al., 2004
Healthy subjects Both Aerobic training 6 mo (4 days/wk) Plasma ELISA = APN Hulver et al., 2002
Healthy non-obese subjects Male Ergometer training 6 wk (5 days/wk) Serum ELISA ↓ APN (At 16 h after the last training session) Yatagai et al., 2003
Young subjects Male Cycle ergometer 2 h (Acute) Plasma ELISA = APN Punyadeera et al., 2005
Highly-trained young rowers Male Rowing ergometer Maximal 6,000 m test (Acute) Plasma ELISA ↑ APN (After 30 min of recovery) Jurimae et al., 2005
Highly-trained young rowers Male Training for rowers 6 mo Plasma ELISA = APN Jurimae et al., 2006
Inactive subjects Male Resistance training (low, moderate, high intensity) 6 mo (3 days/wk) Plasma ELISA = APN (low intensity)
↑ APN (moderate)
↑ APN (high)
Fatouros et al., 2005
Young overweight subjects Male Cycle ergometer 45 min (Acute) Plasma ELISA = APN (Post 24, 48 h) Jamurtas et al., 2006
Obese subjects Both Aerobic exercise + hypo-caloric (ExHypo) or eucoloric (ExEu) diet 12 wk (5 days/wk) Serum
Skeletal muscle
ELISA
PCR
↑ HMW/Total APN
↑ AdipoR1 and 2
O’Leary et al., 2007
Obese subjects Female Aerobic exercise (Bicycle ergometer) 12 wk (5 days/wk) Plasma SCAAT (biopsy) ELISA
PCR
= APN
= APN
Polak et al., 2006
Obese subjects Female Endurance training 7 mo (4–5 days/wk) Plasma ELISA ↑ APN Kondo et al., 2006
Obese adolescents Both Aerobic activities 3 mo (3 days/wk) Plasma ELISA ↑ APN Balagopal et al., 2005
Middle-aged subjects with insulin resistance Both Aerobic exercise (moderate to intense) 16 wk (5 days/wk) Plasma ELISA = APN Marcell et al., 2005
Caucasian subjects with NGT, IGT, and T2D Both Physical training 4 wk (3 days/wk) Serum Skeletal muscle ELISA
PCR
↑ APN
↑ AdipoR1 and 2
Bluher et al., 2006
Caucasian subjects with NGT, IGT, and T2D Both Physical training 4wk (3 days/wk) Subcutaneous AT
Skeletal muscle
PCR
PCR
↑ AdipoR1 and 2
↑ AdipoR1 and 2
Bluher et al., 2007
Caucasian subjects with NGT, IGT, and T2D Both Physical training program (Aerobic + Power training) 4 wk (3 days/wk) Plasma ELISA = APN in NGT
↑ APN in IGT
↑ APN in T2D
Oberbach et al., 2006
Caucasian subjects with NGT, IGT, and T2D Both Physical training (Aerobic exercise) 4 wk (3 days/wk) Plasma
Skeletal muscle
ELISA
PCR
↑ APN in NGT, IGT and T2D
↑ AdipoR1 and 2 in NGT, IGT, and T2D
Bluher et al., 2006
Patients with T2D Both Aerobic exercise (walking and bicycle ergometer) 3 wk (5 days/wk) Plasma ELISA = APN Yokoyama et al., 2004
Middle-aged subjects with T2D Male Endurance training 8 wk (3 days/wk) Plasma ELISA = APN Boudou et al., 2003
Older, healthy subjects Both Aerobic and resistance exercise training 12 wk (3 days/wk) Serum ELISA ↑ APN Markofski et al., 2013
Rats (SD) Male Endurance training 6 mo (5 days/wk) Serum
Skeletal muscle
Adipose
Skeletal muscle
Adipose
ELISA
PCR
PCR
WB
WB
↑ APN
↑ APN
= APN
↑ APN
↑ APN
Dai et al., 2013
Mice (Swiss) Male Swimming exercise 12 wk (5 days/wk) Adipose
Liver
Skeletal muscle
WB ↑ AdipoR1
↑ AdipoR1
↑ AdipoR1
Farias et al., 2012
Mice (db/db) Male Endurance training 10 wk (5 days/wk) Serum ELISA ↑ APN Lee et al., 2011
Mice (KKAy) Male Endurance training 8 wk (5 days/wk) Skeletal muscle
Skeletal muscle
Liver
Liver
White adipose
White adipose
PCR ↑ AdipoR1
= AdipoR2
↑ AdipoR1
↓ AdipoR1
= AdipoR1
= AdipoR1
Huang et al., 2006
Mice (C57BL/6) Male Voluntary wheel running 6 wk Plasma ELISA = APN Bradley et al., 2008

AdipoR, adiponectin receptor; APN, adiponectin; AT, adipose tissue; SCAAT, subcutaneous abdominal adipose tissue; db/db, leptin receptor mutated mouse; ELISA, enzyme linked immunosorbent assay; HMW, high molecular weight; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; PCR, polymerase chain reaction; SD, Sprague Dawley; T2D, type 2 diabetes; WB, western blotting; ↑, increase; ↓, decrease; =, no change.

Table 3.
Effects of calorie restriction (CR), weight loss, and gastric bypass surgery on adiponectin
Subject or animal Sex Type of treatment Duration Tissues Methods Conclusions References
Normal subjects Both CR ≤ 7 yr Serum ELISA ↑ APN Fontana et al., 2010
Normal weight subjects Female CR (1,000–1,200 kcal/day) 4 wk Plasma ELISA ↓ APN Wolfe et al., 2004
Caucasian subjects Male CR
(low calorie diet, 800 kcal/day)
12 wk Serum ELISA ↑ APN Schulte et al., 2013
Obese subjects Both CR program 3 mo Plasma ELISA ↑ HMW APN
↓ hexamer APN
↓ trimer APN
Kobayashi et al., 2004
Obese subjects Female CR (↓ 600 kcal/day) 5–6 mo Adipose
Adipose
Plasma
Adipose
Adipose
Adipose
PCR
ELISA
ELISA
WB
WB
WB
↑ APN
↑ APN
= Total APN
↑ HMW APN
= MMW APN
↓ LMW APN
Rossmeislova et al., 2013
Obese subjects Both CR (weight loss, very low caloric diet) 12 wk Serum ELISA ↑ APN Oberhauser et al., 2012
Obese subjects Female CR (very low calorie diet) 3 wk Serum ELISA = APN Anderlova et al., 2006
Severely obese subjects Female CR (low-calorie diet, less than 5% weight loss or 5–10% weight loss) 3 wk Plasma ELISA = APN (less than 5%)
↑ APN (5–10% weight loss)
Varady et al., 2009
Obese subjects with metabolic syndrome Both CR (very low-calorie diet) 12 mo Plasma ELISA = APN Xydakis et al., 2004
Patients with T2D Both Low calorie diet Roux-en-Y gastric bypass 3 mo Plasma ELISA = APN
↑ APN
Plum et al., 2011
Rats (F344/NSIc) Male CR 4 wk Plasma ELISA = HMW APN Plum et al., 2011
Rats (SD) Male CR (40%) 6 mo Serum
Skeletal muscle
Adipose
Skeletal muscle
Adipose
ELISA
PCR
PCR
WB
WB
↑ APN
↑ APN
↑ APN
↑ APN
↑ APN
Dai et al., 2013
Rats (SD) Male CR (40%) 26 wk Serum ELISA ↑ APN Cerqueira et al., 2012
Rats (SHRs) Male CR 5 wk Plasma ELISA ↑ APN Cerqueira et al., 2012
Mice (C57BL/6) Female CR 8 wk Serum ELISA ↑ APN Wheatley et al., 2011
Mice (C57BL/6N) Female CR (30% caloric-restricted diet) 10 wk Serum ELISA ↑ APN Fenton et al., 2009
Mice (C57BL/6J) Female CR Alternate-day fasting 4 wk Plasma ELISA ↑ APN
↑ APN
Varady et al., 2010
Mice (C57BL/6) Male CR 8 wk Plasma ELISA ↑ APN Wang et al., 2007

APN, adiponectin; CR, calorie restriction; ELISA, enzyme linked immunosorbent assay; HMW, high molecular weight; LMW, low molecular weight; MMW, medium molecular weight; PCR, polymerase chain reaction; SD, Sprague Dawley; T2D, type 2 diabetes; SHRs, spontaneously hypertensive rats; WB, western blotting; ↑, increase; ↓, decrease; =, no change.

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