Review 603

Authors

M. C. F. Passos, M. C. Gonçalves

Affiliation

Institute of Nutrition, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Key words ▶ adiponectin ● ▶ receptors ● ▶ insulin resistance ● ▶ exercise ●

Abstract

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Adiponectin is an adipocyte-derived abundant plasma protein, also called Acrp30 (adipocyte complement-related protein), adipoQ, ApM1 (AdiPose Most abundant Gene transcript 1), or GBP28 (gelatin-binding protein-28). Insulin resistance is a primary contributing factor in the pathogenesis of type 2 diabetes. Adiponectin binds to adiponectin receptors AdipoR1 and

Abbreviations

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Acrp30

received 18.03.2014 accepted 12.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1377026 Horm Metab Res 2014; 46: 603–608 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence Prof. M. C. F. Passos, PhD Instituto de Nutrição Universidade do Estado do Rio de Janeiro Rua São Francisco Xavier 524, bloco D Rio de Janeiro RJ 20550-900 Brazil Tel.: + 55/219/96028 197 Fax: + 55/212/2742 198 [email protected]

Adipocyte complement-related protein of 30 kDa Akt Protein kinase AdipoR1 Adiponectin receptor 1 AdipoR2 Adiponectin receptor 2 AMPK AMP-activated protein kinase ApM1 AdiPose Most abundant Gene transcript 1 APPL1 Endosomal adaptor protein 1 Foxo1 Forkhead box, class O GBP28 28 kDa gelatin binding protein IR Insulin receptor IRS-1 Insulin receptor substrate 1 IRS-2 Insulin receptor substrate 2 MAPK Mitogen-activated protein kinase PPAR-GC1α Peroxisome proliferator-activated receptor gamma coactivator 1-alpha PI3K Phosphatidylinositol 3-kinase PPARα Peroxisome proliferator-activated receptor-α

Introduction

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Adiponectin is an adipokine synthesized and secreted mainly by adipose tissue [1]. However, there are reports that adiponectin is synthesized also by cardiomyocytes, skeletal muscle, osteoblasts, placenta, and pituitary [2–5]. Adiponectin

AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. In the same sense chronic exercise has been showed to induce numerous metabolic factors that can improve insulin resistance. It has been reported that physical exercise training increases adiponectin receptors, which may mediate the improvement of insulin resistance in response to exercise, which is the focus of the present review.

exerts its beneficial effect on metabolism by improving insulin sensitivity, glucose tolerance, and lipid profile, and by decreasing atherosclerosis and inflammation. Adiponectin exerts its effect mainly by activating AMPK, p38 MAPK, and PPARα in skeletal muscle and liver, thereby decreasing the level of glucose and lipids in vivo [6]. The effects of adiponectin are mainly through increase of fatty acid oxidation and glucose uptake in muscle and inhibition of gluconeogenesis in liver [7], which are mediated by 2 membrane receptors, AdipoR1 and AdipoR2, by a direct interaction with the extracellular COOH terminus of these receptors [7]. APPL1 is the first identified protein that interacts directly with its receptors. The PTB domain of APPL1 interacts directly with the intracellular region of adiponectin receptors [8]. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in the insulin-signaling pathway and is an important mediator of adiponectin-dependent insulin sensitivity in skeletal muscle, adipose tissue, liver, and other organs [8]. Hence, APPL1 plays a critical role in the cross talk between adiponectin and insulin signaling pathways. It is well known that exercise enhances insulin sensitivity, probably by increasing the levels of adiponectin and/or its receptors. In addition, it seems that its effects are dependent on physical exercise and could enhance insulin sensitivity by

Passos MCF, Gonçalves MC. Insulin Sensitivity and Adiponectin … Horm Metab Res 2014; 46: 603–608

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Regulation of Insulin Sensitivity by Adiponectin and its Receptors in Response to Physical Exercise

604 Review

raising the expression of adiponectin receptors e intensity or duration [9, 10]. In this review, we will discuss the role of exercise and adiponectin receptors in the regulation of insulin sensitivity.

oxidation due to decrease in hepatic gluconeogenesis and increased muscle glucose uptake [6].

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Adiponectin, also called Acrp30, adipoQ, ApM1, and GBP28 is encoded by a gene located on chromosome 3q27 which contains 3 exons and 2 introns [11–14]. Adiponectin is a protein of 247 amino acids with a predictive mass of 28 kDa, mainly produced by adiposities. This is the most abundant circulating protein produced by the adipose tissue and its secretion is enhanced by insulin [15]. Adiponectin belongs to the complement 1q family and forms a characteristic homomultimer. Adiponectin can be found into five different configurations, which have different biological effects: the globular adiponectin (gAPN), full-length adiponectin (fAPN), low-molecular-weight adiponectin, medium molecular weight adiponectin, and high molecular weight adiponectin (HMW). A small amount of a processed globular form was reported to be present in human plasma [16]. Adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2) are encoded by genes located at chromosome 1p36.13-q41 and 12p13.31, respectively [17]. These 2 receptors are integral membrane proteins with seven transmembrane domains with an internal N-terminal collagenous domain and an external C-terminal globular structure. AdipoR1 has high affinity for gAPN whereas AdipoR2 mainly recognizes fAPN [18]. T-Cadherin (an adiponectin-binding protein) has also been proposed as an adiponectin receptor for the hexameric and HMW forms of adiponectin, but not for the trimeric or globular forms [19].

Decreased expression of AdipoR1 in muscle showed a key role of adiponectin/AdipoR1 in the regulation of insulin resistance [27]. Obesity and consequently hyperinsulinemia are associated with decreased expression of AdipoR1/R2 mRNA levels, thereby reducing adiponectin sensitivity and causing insulin resistance. Moreover, hyperinsulinemic ob/ob mice present lower expressions of both AdipoR1 and AdipoR2 in muscle and adipose tissue [28]. In 2004, Tsuchida et al. [28] suggested that strategies to increase Adipo R1/R2 could provide a new treatment for insulin resistance and type 2 diabetes. More recently, it was demonstrated that APPL1 also plays a key role in regulating metabolism and insulin sensitivity by mediating adiponectin signaling [8]. In the adiponectin-signaling cascade, the APPL1 transmits signals from adiponectin receptors to respective targets by directly interacting with the NH2-terminal intracellular region of AdipoR1 and AdipoR2 [8]. These authors [8] demonstrated that overexpression of APPL1 stimulates insulin-mediated Akt phosphorylation, whereas overexpression of APPL1 mutant significantly reduces this effect. In db/db mice, adiponectin-induced vasodilatation is significantly lower than in their controls, and the expression of APPL1 mRNA is decreased in small mesenteric arteries [29]. This suggests a direct association between lower APPL1 expression and impaired vasodilatation, which is associated with endothelial dysfunction in diabetes. These results are new insights in the study of factors like exercise and new drugs that can modulate the expression and function of APPL1 in insulin target tissues.

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Adiponectin and Insulin Resistance

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Adiponectin is well defined as an antidiabetic and anti-atherogenic adipokine. Adiponectin acts through 2 transmembrane receptors, AdipoR1 and AdipoR2, interacting with the COOHterminal extracellular part of AdipoR1 [8]. AdipoR1 is more abundantly expressed in muscles while AdipoR2 predominates in the liver. AdipoR1 and AdipoR2 serve as the major receptors for adiponectin in vivo, with AdipoR1 activating the AMPK pathways and AdipoR2 activating the PPAR-α pathway [20]. The decrease in adiponectin levels is particularly related to increased intra-abdominal fat [21]. In addition, plasma adiponectin levels are shown to be reduced in a number of conditions frequently associated with insulin resistance, such as, cardiovascular diseases, hypertension, or metabolic syndrome [22, 23]. The mechanisms involved may include suppressive effects of inflammatory cytokines, and/or downregulation by hyperinsulinemia or lipid accumulation in adiposities [21, 24]. Since 2001, the Yamauchi’s group [25] observed that lower serum adiponectin levels in murine models of type 2 diabetes were partially restored by replenishment of recombinant adiponectin. Later, in 2002, the Stefan’s group showed that the adiponectin increased insulin receptor tyrosine kinase activity in skeletal muscle and increased the expression of proteins involved in fatty acid metabolism [26]. The mechanism by which adiponectin mediates enhanced insulin sensitivity is associated with the increased fatty acid oxidation, via activation of AMPK and PPAR-α, carrying reduced glucose levels and increased fatty acid

Regulation of Adiponectin Receptors

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Food intake Advanced age and high-fat feeding, both of which are factors that predispose humans to obesity and insulin resistance, are associated with decreasing adiponectin and increasing AdipoR1 and/or AdipoR2 levels [30]. On the contrary, caloric restriction (CR) did not alter tissue or cellular AdipoR1 and AdipoR2 expression in rats, but led to an increase in adiponectin mRNA levels [31]. The levels of AdipoR1 and AdipoR2 mRNA expression in the liver and skeletal muscle increased after fasting, and refeeding rapidly restored these to levels equal to the original fed state [28].

Insulin AdipoR1 and AdipoR2 mRNA increased significantly in skeletal muscle of hypoinsulinemic/hyperglycemic mice treated with streptozotocin, and both AdipoR1 and AdipoR2 mRNA were completely restored by insulin treatment. These observations suggested that insulin might negatively regulate AdipoR1/R2 mRNA levels [28, 31]. However, Li et al. [32] showed that improvement of insulin sensitivity by thiazolidinediones is not related to AdipoR1/R2 expression changes. The expressions of both AdipoR1 and AdipoR2 were significantly decreased in muscle and adipose tissue of insulin resistant ob/ob mice [28]. Moreover, adiponectin induced activation of AMPK was impaired in skeletal muscle of ob/ob mice. These data suggest that adiponectin resistance was observed in ob/ob mice,

Passos MCF, Gonçalves MC. Insulin Sensitivity and Adiponectin … Horm Metab Res 2014; 46: 603–608

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Adiponectin Receptors and Insulin Resistance Molecular Structure of Adiponectin

which exhibited decreased expression levels of AdipoR1 and AdipoR2 [33]. In humans, Debard et al. [34] have reported that adiponectin receptor expression in skeletal muscle of type 2 diabetic patients was decreased. Therefore, a correlation has been reported between adiponectin receptor gene expression and insulin sensitivity in nondiabetic Mexican Americans with or without a family history of type 2 diabetes [35]. It has been suggested that insulin suppresses the activity of FoxO1, a suppressor of PPAR␥, which is an inducer of adiponectin biosynthesis. Indeed, serum adiponectin levels are elevated in type 1 diabetic patients (i. e., patients with reduced levels of circulating insulin) as well as in patients with genetically defective insulin receptors when compared with healthy controls [36]. Thus, the strategies to increase AdipoR1/R2 may be a logical approach with which to provide a novel treatment modality for insulin resistance and type 2 diabetes.

Physical Exercise

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Christiansen et al. [37] have demonstrated, that in males and females, diet-induced weight loss and exercise alone or in combination increases the expression of adiponectin receptors in adipose tissue and skeletal muscle. Adiponectin receptor expressions in skeletal muscle [9] and adipose tissue [38] are increased in conditions of insulin resistance and type 2 diabetes, and an exercise intervention for 4 weeks, which improves metabolic parameters also increases circulating adiponectin levels and upregulates expression of both adiponectin receptors. However, the improvement of insulin sensitivity by thiazolidinediones is not related to AdipoR1/R2 expression changes [39].

Physical Exercise and Adiponectin

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Adiponectin reduces the postprandial increase in plasma free fatty acids and affects hepatic glucose output [6, 7]. The exercise as well as adiponectin are associated with a higher percentage of fatty ▶ Fig. 1). acid oxidation and greater carbohydrate utilization (●

Fig. 1 Physical exercise can lead to weight loss and increase adiponectin, which can activate AMPK and PPARα in the liver and skeletal muscle. Additionally, physical exercise can increase adiponectin receptors, AdipoR1 and AdipoR2, which interact with APPL1 that bind the N-terminal intracellular domains of the receptors. In skeletal muscle AdipoR1 activates AMPK and thereby stimulating phosphorylation of ACC, fatty acid oxidation, and glucose uptake. AdipoR1 activates PPARα, thereby also stimulating fatty acid oxidation and decreasing tissue TG content in muscle. In the liver, AdipoR2 activates AMPK, thereby reducing molecules involved in gluconeogenesis and increasing phosphorylation of ACC and fatty acid oxidation. AdipoR2 activates PPARα, thereby stimulating fatty acid oxidation and decreasing tissue TG content in the liver. These alterations all increase insulin sensitivity. WAT: White adipose tissue; PEPCK: G6Pase: glucose-6-phosphatase G6Pase.

In overweight males, the short-term exercise training increased plasma adiponectin levels (260 % above baseline values) despite unchanged body weight [44]. Thus, studies of acute short-term exercise demonstrate that plasma adiponectin concentrations do not change in response to moderate running or cycling in healthy subjects. Other results suggest that adiponectin concentration is altered in response to maximum acute exercise in highly trained athletes. Furthermore, another study showed that adiponectin concentration could increase after short-term exercise in overweight males. Thus, these data suggest that these discrepancies may be due to subject status, such as training, body weight, or the kind of fed state of exercise (cycling, running, rowing).

Acute Exercise

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The effects of acute exercise on adiponectin levels are variable. Some studies [40, 41] investigated the acute effects of shortterm exercise (running and cycling) on adiponectin concentration in healthy subjects but observed no changes. Another study by Jurimae et al. [42] has determined the adiponectin concentration in trained male rowers, who completed a 6 000 m rowing ergometer test. Adiponectin was decreased immediately after the exercise, when adjusted for plasma volume changes, and significantly increased after 30 min of recovery. Later, these authors determined acute adiponectin response to a 6.5 km rowing at the individual anaerobic threshold in trained athletes. Adiponectin was unchanged immediately after the exercise and significantly increased after 30 min of recovery [43]. The authors concluded that plasma adiponectin is sensitive in the first 30 min of recovery to the effects of short-term exercise at individual anaerobic threshold when all major muscle groups are involved.

Chronic Exercise

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The effect of chronic on adiponectin levels is also variable and this variability may be due of the intensity and duration of exercise.

Short-term training Lim et al. [45] studied healthy young (22.4 ± 2.8 years) and middle aged (59.8 ± 5.9 years) women, who performed 60 min of aerobic exercise 3 times per week at 70 % maximal exercise capacity. After a 10-week training program, serum adiponectin concentrations were increased in both groups. The authors concluded that the improved insulin sensitivity could involve increased adiponectin levels in trained women.

Long-term training Resting as well as exercise responses to 2 000 m sculling were measured before and after training in elite rowers who com-

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Review 605

pleted a 6-month training program [46]. No changes were observed in resting adiponectin levels, but were significantly reduced after exercise. The authors [46] concluded that training might change the adiponectin response to exercise. However, others have failed to report such changes in a similar population during or after prolonged exercise [47]. These are one of the few training studies that have been conducted with normal young men. Other studies have examined the effect of long-term training on adiponectin in older populations or those with obesity and diminished insulin sensitivity. In a study on older obese subjects (mean age 63 years), who completed 12 weeks of aerobic training, the plasma adiponectin levels did not change despite the reversal of insulin resistance [48]. The authors surmised that exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat. On the other hand, in obese adolescent girls, 12-week aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, and adiponectin [49]. Shadid et al. [50] analyzed plasma adiponectin concentrations in upper-body obese insulin resistant, nondiabetic adults before and after 19 weeks of programmed diet/exercise. They reported that this therapy reduced body fat visceral fat and improved insulin sensitivity and adiponectin. These data indicated that adiponectin was consistently related with body fat distribution. Corroborating these findings, Kondo et al. [51] showed that a 7-month exercise program decreased BMI, percentage fat, and increased adiponectin levels in young obese females. Thus, the duration and intensity of this exercise-training program was sufficient to reduce body fat and increase adiponectin concentrations in young obese female subjects. Individuals with severe obesity (mean BMI = 45.8 kg/m2), who completed a 15-week exercise program and a hypocaloric diet presented reduction of body weight, increased insulin sensitivity, and plasma adiponectin. However, the physical treatment did not affect adiponectin receptor 1 and 2 mRNA in adipose tissue or skeletal muscle [52]. So, dietary modification with exercise appears to be responsible for the increased serum adiponectin in severe obesity. Thus, a number of training studies have been conducted with different populations, including obese men and women, adolescents, older subjects, and elite rowers. These studies reveal that exercise training, which results in weight loss may increase adiponectin levels.

exercise training may reverse reduced AdipoR1 gene expression in soleus muscle and improve insulin sensitivity in the obese Zucker rats. In 2007, Zeng et al. [10] have also reported that longterm exercise (25 m/min for 30 min, 5 days/week for 12 weeks) is required to increase AdipoR1 mRNA levels in muscle of rats. In humans, Kriketos et al. [44] showed that short-term exercise training (1 week) increased adiponectin levels in overweight males, but they did not investigate the adiponectin receptors. Bluher et al. [9] reported in humans that physical exercise training (4 weeks) increases mRNA expression of adiponectin receptors in muscle, which may mediate the improvement of insulin resistance in response to exercise. Later, the same authors [38] showed that AdipoR2 mRNA expression in subcutaneous and visceral adipose tissue is reduced in states of obesity and type 2 diabetes. AdipoR2 mRNA expression in fat is correlated with circulating adiponectin levels, lipid levels, parameters of insulin sensitivity, and glycemic control. An exercise intervention for 4 weeks resulted in increased expression of adiponectin receptors, which may thus mediate the beneficial effects of exercise on insulin resistance, glycemia, and lipidemia [38]. Although studies on this topic are scarce in humans, exercise training is probably helpful for individuals with insulin resistance. The effect of exercise training on adiponectin receptor expression was also demonstrated in KKAy mice, an animal model of spontaneous diabetes [60]. This study showed that 8-week exercise training reduced the HOMA-R and plasma glucose levels and increased mRNA expression of AdipoR1 in both skeletal muscle and liver in KKAy mice. These results indicate that chronic exercise training plays a beneficial role in the improvement of insulin resistance in KKAy mice. This increase in AdipoR1 expression might play a beneficial role in the improvement in insulin sensitivity through the PPAR-α independent and dependent pathways in muscle and liver, respectively [60]. More recently, studies with normal mice showed that exercise training improves insulin action through increased adipoR1–2/ APPL1 protein in the hepatic, adipose, and skeletal muscle tissues [61, 62]. Thus, based on the above studies it is likely that the expression of adiponectin receptors is regulated in target organs of insulin such as skeletal muscle and liver by exercise training, and this might promote the action of adiponectin to improve insulin sensitivity.

Adiponectin and Adiponectin Receptors as Therapeutics Targets Physical Exercise and Adiponectin Receptors

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Physical exercise is associated with increased insulin sensitivity in several tissues. Over the past several years, considerable progress has been made in understanding the molecular basis for these clinically important effects of physical exercise. As described earlier, increased adiponectin levels can improve insulin sensitivity [8]. Both adiponectin receptors, AdipoR1 and AdipoR2, are expressed in human adiposities [39, 53, 54] and muscle cells [9]. AdipoR1 and AdipoR2 interact with APPL1, which bind the N-terminal intracellular domains of the receptors and thus regulates the activity of Akt [1]. In skeletal muscle, AdipoR1 activates AMPK [55] and PPAR-GC1α, as well as Ca21 signaling pathways [56], which have also been shown to be activated by exercise [57, 58]. Some authors reported that exercise improves insulin signaling in different tissues through increased levels of adiponectin receptors and APPL1. Chang et al. [59] showed that long-term

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Regarding the effect of adiponectin on insulin resistance, an upregulation of plasma adiponectin and/or adiponectin receptors, or the development of adiponectin agonists may be of interest in the prevention and/or treatment for insulin resistance and type 2 diabetes. As we have described previously, exercise seems capable of modulating adiponectin and/or adiponectin receptors production and could be of importance in the prevention of insulin resistance.

Development of AdipoR Agonists

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Adiponectin improved insulin resistance and glucose intolerance via multiple mechanisms including activation of AMPK, decreased oxidative stress, and decreased tissue triglyceride content [6].

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606 Review

Recently, Okada-Iwabu et al. [63] have reported the identification of an orally active agonist AdipoR (AdipoRon), which binds to both AdipoR1 and Adipo R2. AdipoRon showed very similar effects to adiponectin in muscle and liver, as the activation of AMPK and PPAR-α pathway, and improved insulin resistance in AdipoR1-R2 double knockout mice. The main effects of the AdipoR1 and AdipoR2 agonists (AdipoRon) in target tissues are increased mitochondrial biogenesis, exercise endurance, genes expression involved in fatty acid combustion, and decreased oxidative stress in skeletal muscle. In liver, AdipoRon decreases gene expression involved in gluconeogenesis, oxidative stress and increases genes involved in fatty acid combustion. In white adipose tissue, it reduces oxidative stress, proinflammatory cytokines and the accumulation of M1 macrophages. These effects result in increased insulin sensitivity and glucose tolerance. Furthermore, AdipoRon prolonged shortened lifespan of db/db mice [63]. Orally active AdipoR agonists are a promising novel therapeutic approach for treating obesity-related disorders such as type 2 diabetes.

Conclusion

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Despite the discrepancies, most of the studies discussed in this review led us to conclude that the improvement of insulin sensitivity by physical exercise is related to adiponectin and/or AdipoR1/R2 expression changes. The studies showed that long-term physical exercise could enhance insulin sensitivity by raising the expression of adiponectin receptors, AdipoR1 and AdipoR2, which activates the AMPK and PPAR-α pathways, respectively. It is likely that the expression of adiponectin receptors is regulated in target organs of insulin such as skeletal muscle and liver by exercise training, and this might promote the action of adiponectin to improve insulin sensitivity. In addition to physical exercise, a recent study showed that active AdipoR agonists (AdipoRon) are a promising therapy to improve insulin sensitivity. AdipoRon action resulted in reduced tissue triglyceride content in liver and muscle, and oxidative stress in liver, muscle and WAT, and decreased inflammation in liver and white adipose tissue. Thus, the physical exercise and AdipoR active agonists could be a new strategy for treatment of type 2 diabetes. Further studies will be required to clarify the mechanisms by which adiponectin receptors are regulated during physical exercise.

Conflict of Interest

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The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

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Passos MCF, Gonçalves MC. Insulin Sensitivity and Adiponectin … Horm Metab Res 2014; 46: 603–608

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