Best Practice & Research Clinical Endocrinology & Metabolism xxx (2013) 1–9
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Adiponectin action in skeletal muscle Ying Liu, Ph.D., Postdoctoral Fellow in Physiology a, Gary Sweeney, Ph.D., Professor in Biology b, * a b
Department of Physiology, University of Toronto, Toronto, Canada Department of Biology, York University, Toronto, ON M3J 1P3, Canada
Keywords: adiponectin skeletal muscle receptors signaling metabolism autocrine endocrine myokine adiponectin resistance therapeutic
The beneficial metabolic effects of adiponectin which confer insulin-sensitizing and anti-diabetic effects are well established. Skeletal muscle is an important target tissue for adiponectin where it regulates glucose and fatty acid metabolism directly and via insulin sensitizing effects. Cell surface receptors and the intracellular signaling events via which adiponectin orchestrates metabolism are now becoming well characterized. The initially accepted dogma of adiponectin action was that the physiological effects were mediated via endocrine effects of adipose-derived adiponectin. However, in recent years it has been established that skeletal muscle can also produce and secrete adiponectin that can elicit important functional effects. There is evidence that skeletal muscle adiponectin resistance may develop in obesity and play a role in the pathogenesis of diabetes. In summary, adiponectin acting in an autocrine and endocrine manner has important metabolic and insulin sensitizing effects on skeletal muscle which contribute to the overall anti-diabetic outcome of adiponectin action. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The prevalence of obesity and diabetes has grown to epidemic proportions over the past thirty years, principally as a consequence of prolonged high carbohydrate- and high fat- containing diet in combination with decreased physical activity, and with this an alarming increase in the incidence of type 2 diabetes has emerged [1]. Research efforts to discover the various potential mechanisms linking
* Corresponding author. Tel.: þ1 416 736 2100; Fax: þ1 416 736 5698. E-mail address: [email protected] (G. Sweeney). 1521-690X/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2013.08.003
Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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obesity with diabetes have proliferated exponentially and we now have a solid understanding of many underlying pathophysiological events. In particular, the focus on various adipose-derived factors has yielded intriguing findings and in this article we focus on adiponectin. Notably, publications over the last two decades have documented numerous beneficial effects of adiponectin, including anti-diabetic, anti-inflammatory and cardioprotective outcomes [2–5]. This has generated great interest in understanding the precise mechanisms of adiponectin action and identifying opportunities for therapeutic exploitation [5–7]. Adiponectin is somewhat unique amongst adipokines in that despite the increasing mass of adipose tissue in the obese population, a decreased circulating level of adiponectin was observed and correlated strongly with various features of the metabolic syndrome [4,5]. Adiponectin circulates abundantly (w2–20 ug/ml) as a combination of different oligomeric forms, which include the low molecular weight (LMW, trimeric) form, the albumin binding LMW form, the medium molecular weight (MMW, hexameric) form and the high molecular weight (HMW, oligomeric) form. The mixture of these oligomeric forms is often referred to as full length adiponectin (fAd). An additional form, globular adiponectin (gAd), which contains only the C-terminal globular domain of adiponectin can also mediate biological effects. gAd can be generated by enzymatic cleavage of adiponectin, which can be mediated by leukocyte-derived elastase [8]. Hence, it is speculated that gAd generation may be most prominent at sites of inflammation. In this review we focus on the importance of skeletal muscle in adiponectin action with an emphasis on current perspectives and pertinent research questions. Metabolic effects of adiponectin in skeletal muscle It is apparent that adiponectin has widespread beneficial metabolic effects and the majority of studies have emphasized the importance of hepatic actions of adiponectin [4,5]. Importantly, many studies have clearly demonstrated that skeletal muscle is an important peripheral target tissue for adiponectin to exert its beneficial metabolic effects and contribute to anti-diabetic action. Early work in cultured mouse or rat skeletal muscle cells found that adiponectin increased glucose uptake and regulated the subsequent metabolic fate [9–13]. Similar findings were made in primary human skeletal muscle cells [14] and muscle strips from human patients [15]. We recently performed an unbiased metabolomic profiling approach to determine the metabolic changes occurring in skeletal muscle from adiponectin knockout mice fed a high fat diet, then treated with or without adiponectin [16]. It is believed that understanding changes in metabolite profiles will serve several purposes, including conferring an improved understanding of the primary mechanisms resulting in metabolic dysfunction and identifying potential opportunities for better biomarker detection [17]. Data demonstrated that the majority of high fat diet-induced changes in metabolite profiles from multiple metabolic pathways were normalized upon adiponectin supplementation [16]. The receptors and downstream signalling events via which adiponectin regulates glucose uptake in muscle have been characterized (Fig. 1). Briefly, adiponectin receptor 1 (AdipoR1) and AdipoR2 appear to be the main adiponectin receptor isoforms involved [4,5,18] although T-cadherin may have a role in binding adiponectin and facilitating signaling in skeletal muscle [19,20]. The adaptor protein containing pleckstrin homology domain, phosphotyrosin binding (PTB) domain and leucine zipper motif (APPL1) is the first and thus far best characterized adaptor protein which binds to adiponectin receptors [21,22]. Adiponectin stimulates glucose uptake in muscle via causing translocation of the glucose transporter GLUT4 to the cell surface [9] and this effect was abolished upon knockdown of APPL1 using siRNA [22]. An important downstream target of AdipoR/APPL1 signaling is AMPK which mediated many biological effects of adiponectin [4,5]. In addition to directly stimulating glucose uptake and metabolism, adiponectin enhances insulin sensitivity in muscle [23]. A potential mechanism for crosstalk between adiponectin and insulin signalling is the adiponectinmediated inhibition of p70 S6 kinase mediated serine phosphorylation of IRS1 at Ser302 and Ser636/639 via LKB1/AMPK/tuberous sclerosis 1/2 (TSC1/2) signalling [24]. The ability of adiponectin to enhance insulin stimulated phosphorylation of Akt was attenuated upon overexpression of dominant negative AMPK [24]. Studies in mouse models have further investigated the role of AdipoRs and other components of the adiponectin signalling pathway in regulating peripheral glucose homeostasis. For example, initial characterization of adiponectin knockout mice produced Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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independently by several groups showed a relatively normal phenotype with only mild or moderate insulin resistance, until challenged with high fat diet when knockout mice developed exaggerated metabolic dysfunction [25–27]. Simultaneous deletion of both AdipoR1 and R2 prevented adiponectin binding and correlated with increased triglyceride content in various tissues, development of insulin resistance, hyperinsulinemia and marked glucose intolerance [28]. AdipoR1 KO mice showed decreased glucose tolerance associated with defects in AMPK activation [28,29] whereas AdipoR2 KO mice were found in one study to have better glucose tolerance and lipid profiles compared with control mice [29]. However, upon prolonged high-fat feeding, pancreatic beta-cell failure ensued and glucose homeostasis deteriorated. Skeletal muscle specific deletion of AdipoR1, as expected, decreased glucose disposal rate [30]. Electrotransfer-mediated overexpression of APPL1 in rat skeletal muscle resulted in enhanced insulin-stimulated glucose disposal [31]. Crosstalk with not only insulin signaling but also other adipokines may be an underappreciated regulatory step in adiponectin action. Co-culture studies conducted by using primary rat adipocytes and rat skeletal muscle cells confirmed the importance of adiponectin in the regulation of glucose uptake in skeletal muscle cells [32,33]. Co-culture with primary rat adipocytes elevated glucose uptake by skeletal muscle and this response was blunted upon antibody-mediated neutralization of adiponectin or knockdown of AdipoR2 in muscle cells. Notably, adiponectin in this co-culture environment was more potent than recombinant fAd in eliciting glucose uptake, suggesting that the more physiological co-culture environment facilitated adiponectin action [33]. Furthermore, the adipokine profile secreted by primary rat adipocytes form diabetic rats contained less HMW adiponectin and correlated with less glucose uptake in muscle [32]. Thus, the ultimate functional effect of adiponectin on skeletal muscle appears to be highly dependent upon the existing intra- and extra-cellular environment at any given time. Adiponectin also regulates fatty acid metabolism in muscle and has been shown to increase fatty acid uptake and oxidation and suppress fatty acid synthesis through the activation of AMPK, p38 MAPK and PPARa [10,11,34,35]. Adiponectin’s ability to up-regulate fatty acid oxidation is supported by gain/loss of function studies where overexpression/knockdown of AdipoRs showed an enhanced/ suppressed fatty acid oxidation, with correlative changes in respective signaling pathways in myocytes [18]. In addition to direct effects on substrate metabolism, adiponectin can also improve mitochondrial bioenergetics, including induction of skeletal muscle biogenesis [30,36,37]. Adiponectin can induce a fiber type switch to provide more oxidative capacity through an AMPK-myocyte enhancer factor 2C (MEF2C)-PGC1a pathway [36]. Indeed, the potential for adiponectin to control myogenesis by regulating proliferation, differentiation and fusion of skeletal muscle precursors, and even dictating muscle fiber type profiles, now appears to be an important functional consequence of adiponectin action with potential significance in several disease states where muscle regeneration is needed [30,38–42]. Interestingly, numerous studies have shown a correlation between gender and adiponectin action. Male individuals typically have lower levels of circulating oligomeric adiponectin forms compared to female individuals due to an interaction between adiponectin and the sex hormone testosterone [43]. There were strong inverse associations between circulating HMW adiponectin and intramyocellular lipid content measured using proton magnetic resonance spectroscopy in human skeletal muscle [44]. Serum adiponectin was positively associated with AMPK phosphorylation and glucose uptake and negatively associated with ceramide content in skeletal muscle of healthy, young, lean men, but not in women [42]. Furthermore, women had lower AdipoR1 expression in skeletal muscle and a lower percentage of type 2 glycolytic muscle fibers than men [42]. The sex-dependent changes in adiponectin levels and action have now been highlighted in several studies and should perhaps be borne in mind as an important consideration in future studies. Adiponectin as an adipokine and myokine The physiological significance of adipokines is well established and, in an analogous fashion, we now appreciate that a similar phenomenon exists with respect to skeletal muscle [45]. Indeed, numerous proteomics-driven studies have recently begun to characterize the muscle secretome (or myokinome) and the changes which occur under pathophysiological conditions, or in vitro conditions Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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mimicking these [45,46]. Although adipocytes are the principal source of circulating adiponectin, several studies have now uncovered the potential for adiponectin production by skeletal muscle and other cell types [23,41,47–51]. To address the potential significance of adiponectin as a myokine, initial experiments set out to examine adiponectin expression in skeletal muscle, determine the changes in adiponectin expression in skeletal muscle from obese/diabetic animal models and to use gain or loss of function approaches to determine the functional significance. Adiponectin messenger RNA and protein was observed in mouse skeletal muscles and cultured skeletal muscle cell lines [41]. There was a relationship between adiponectin expression and fiber type or intramyocellular lipid. Adiponectin expression was highest in type IIA or IID fibers and the majority of fibers with high adiponectin levels also showed elevated intramyocellular lipid [41]. Notably, muscle-derived adiponectin was shown to correlate with muscle function. Upon in situ muscle stimulation, lower peak tetanic forces were detected in adiponectin knockout mice relative to wild type. No change was observed in low-frequency fatigue rates [41]. Thiazolidinediones are well known to mediate anti-diabetic effects at least in part by stimulating adiponectin production by adipocytes. Rosiglitazone has now also been shown to elevate adiponectin synthesis and secretion by skeletal muscle cells and this directly correlated with direct activation of adiponectin signaling and rosiglitazone-mediated improvement in insulin sensitivity [23,47]. Furthermore, rosiglitazone treatment also attenuated the reduced skeletal muscle adiponectin levels observed in high-fat high-sucrose fed rats [23]. Genetic manipulation to produce transgenic mice with enhanced PPAR-gamma activity in skeletal muscle also increased adiponectin expression in this tissue and conferred protection from high fat diet-induced insulin resistance [47]. Further direct evidence of the functional significance of adiponectin production in skeletal muscle in regulation of metabolism was provided by studies in which skeletal muscle cells were engineered to overexpress the adiponectin gene. These cells synthesized and secreted more adiponectin than control cells which directly induced glucose uptake and increased insulin sensitivity [23]. The same phenomena was observed in a mouse model in which the adiponectin gene was specifically overexpressed in skeletal muscle using ultrasound targeted microbubble delivery. Adiponectin overexpression in skeletal muscle increased insulin sensitivity in this tissue and attenuated high fat diet-induced defects in peripheral glucose homeostasis [52]. Study of muscle from adiponectin knockout mice found evidence of enhanced oxidative stress, lipid peroxidation and apoptosis and these abnormalities could be corrected by electrotransfer-mediated restoration of adiponectin expression in the muscle [50]. Hence, it is now clear that adiponectin is produced by skeletal muscle, and its level changes in disease states. The muscle-derived adiponectin not only has important autocrine and/or paracrine effects but may also elicit endocrine effects in other target tissues, such as liver. Adiponectin resistance The development of insulin resistance in skeletal muscle is well accepted as a major contributor to type 2 diabetes. The concept of adiponectin resistance has been mooted and there is strong likelihood that it has important significance in certain pathologies. For example, adiponectin’s metabolic effects in human skeletal muscle were blunted in tissue from obese individuals and feeding a diet high in saturated fats attenuated adiponectin-stimulated signalling and fatty acid metabolism in rodent skeletal muscle [53–55]. It has been proposed that adiponectin resistance precedes lipid accumulation and further metabolic disturbances induced by lipotoxicity [56]. There are several potential mechanisms which may lead to adiponectin resistance, for example reduced expression of one or more adiponectin receptors. Insulin may be an important regulator of adiponectin sensitivity since insulin administration reduced AdipoR expression in several tissues of streptozotocin-induced diabetic mice [57]. Insulin also decreased AdipoR1 levels in cultured skeletal muscle cells, although contrasting effects have been reported on AdipoR2 [57,58]. Interestingly, high glucose conditions were also found to reduce AdipoR1 and AdipoR2 expression in L6 cells [58]. Skeletal muscle AdipoR levels were reduced in ob/ob mice and this led to decreased adiponectin binding to skeletal muscle membrane fractions and functional adiponectin resistance. When adiponectin resistance occurs in the face of normal AdipoR expression, altered expression or posttranslational modification of signalling intermediates in skeletal muscle may also dictate cellular sensitivity to adiponectin [14,21,59,60]. This question should be more rigorously tested in the near future. The regulation of AdipoRs has been recently reviewed [61] and it is Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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intriguing to note that exercise increased expression of APPL1 [62,63], an effect which may at least in part explain the resultant beneficial metabolic effects [64]. Nevertheless, another study showed that chronic exercise training did not improve high fat diet-induced adiponectin resistance in rats [53]. APPL1 expression and phosphorylation on Ser401 was found to be enhanced in obese individuals with type 2 diabetes, perhaps as part of a compensatory mechanism, and levels were reduced after bariatric surgery [65]. It is generally accepted that effects of adiponectin on skeletal muscle mitochondria contribute to improved metabolism. However, somewhat unexpectedly, a study in which muscle biopsies from diabetic patients were treated with adiponectin indicated no significant change in skeletal muscle mitochondrial bioenergetics and adiponectin resistance was proposed as a potential explanation [66]. Although adipocytes and myocytes are often the focus of inter-organ crosstalk, some recent evidence suggests that cardiac and skeletal muscle interactions may have been much underappreciated [67]. A study of skeletal muscle biopsies from patients with chronic heart failure or healthy individuals showed that muscle of the former group had 5-fold elevated muscle adiponectin mRNA levels but significantly reduced AdipoR1 expression, again suggesting the possible existence of adiponectin resistance [51]. Overall, there is evidence that adiponectin resistance occurs in skeletal muscle under certain pathological conditions although the contribution of adiponectin resistance versus adiponectin deficiency towards diabetes needs to be more thoroughly investigated. Potential therapeutic applications of targeting adiponectin action in skeletal muscle The well documented widespread beneficial physiological actions of adiponectin spanning diabetes, inflammation, cardiovascular diseases and cancer have provided much impetus for discovery and development of adiponectin-based therapeutics [68]. Since synthesis and administration of recombinant forms of adiponectin has not proven to be a viable therapeutic approach, largely due to the cost of synthesizing correctly posttranslationally modified bioactive forms, there is a clear need for discovery of compounds which mimic or enhance adiponectin action. There have been reports of several adiponectin-mimetic small molecules at various stages of the drug discovery pipeline, however specific adiponectin-like or adiponectin-sensitizing therapeutics are not yet available. Interestingly, a variety of patents pertaining to adiponectin now exist and one recent addition describes an agent for oral administration comprising adiponectin as an active ingredient (patent publication number: US 2012/ 0115776 A1). It should also be pointed out that several existing drugs, notably thiazolidinediones, and various natural compounds such as dietary fish oils, osmotin and resveratrol can all act at least in part by enhancing adiponectin levels [69,70]. For example, fish oil-derived n-3 polyunsaturated fatty acids prevented defects in adiponectin action in soleus muscle that had been induced by feeding a diet rich in saturated fats [71]. With regard to skeletal muscle, the tissue content of adiponectin was increased by thiazolidinedione treatment in rats [23] and the ultrasound targeted microbubble delivery of adiponectin gene to overexpress specifically in skeletal muscle conveyed anti-diabetic effects [52]. Thus, a potentially promising therapeutic approach may be targeting the myokine properties of adiponectin. This may be achieved with the continued development of therapeutic approaches to specifically target genes or compounds to skeletal muscle [72–74]. Summary The anti-diabetic effects of adiponectin are well characterized and regulation of skeletal muscle metabolism is an important contributory mechanism. The AdipoR isoforms and APPL1-dependent downstream signalling events play a vital role in adiponectin’s metabolic effects in muscle. When circulating adiponectin levels fall or skeletal muscle becomes resistant to adiponectin action the lack of proper glucose and fatty acid homeostasis in muscle contributes to the development of diabetes. An interesting facet to emerge in recent years is that adiponectin is also a myokine, being produced and released by skeletal muscle and mediating functional effects on insulin sensitivity, metabolism and myogenesis. The clinical significance of our current understanding of adiponectin biology is two-fold; first, because adiponectin can be regarded as a robust biomarker for identifying individuals with metabolic syndrome and secondly because adiponectin is an attractive therapeutic target. Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
Fig. 1. Schematic representation depicting regulation of energy metabolism by adiponectin in skeletal muscle Adiponectin exerts its beneficial effect on the regulation of skeletal muscle energy metabolism by various mechanisms, including increasing basal and insulin stimulated glucose uptake via GLUT4 translocation and fatty acid uptake and oxidation directly or indirectly through mitochondrial biogenesis. The increased rate of lipid and glucose clearance due to adiponectin will also eventually lead to enhanced insulin sensitivity via the combination of effects resulting from decreased inflammation, decreased ROS production and improved mitochondrial function. ROS: reactive oxygen species; IRS1/2: insulin receptor substrate 1/2; Akt: protein kinase B; PI3K: phosphatidylinositol 3 kinase; PDK1: 3-phosphoinositide-dependent protein kinase 1; mTOR: mammalian target of rapamycin; S6K: p70 S6 kinase; Rheb: Ras homolog enriched in brain; TSC1/2: tuberous sclerosis complex; LKB1: liver kinase B1; Rab5: Ras in the brain 5; CaMKKb: Ca2þ/calmodulin dependent protein kinase kinase beta; PGC1a: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Sirt1: silent mating type information regulation 2 homolog 1; PPARa: peroxisome proliferator-activated receptor alpha; Acox: acyl-CoA oxidase 1; Ucp2: uncoupling protein 2.
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Practice points Despite significant improvements in the arsenal with which diabetes can be treated there are still significant unmet needs. Lessons learned from clinical studies, animal models and molecular studies suggest, for the most part, that adiponectin mediates anti-diabetic effects. Thus, it would be advantageous to develop approaches to increase adiponectin levels or enhance adiponectin action for the treatment of diabetes. Use of adiponectin based therapeutics may become reality in the near future. Adiponectin, in particular the HMW form, can be considered as a robust biomarker for metabolic syndrome.
Research agenda Further studies are needed to clarify the functional significance of adiponectin produced by skeletal muscle. We must understand if the local pool of adiponectin acts in the same way or in a different manner compared with the circulating pool of adiponectin. Does generation of globular adiponectin represent a physiologically significant regulatory step in adiponectin action? We should investigate when and how adiponectin resistance occurs and if it is tissue specific. Drug discovery programs should be designed to identify small molecules that enhance or mimic adiponectin action.
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Adiponectin action in skeletal muscle Ying Liu, Ph.D., Postdoctoral Fellow in Physiology a, Gary Sweeney, Ph.D., Professor in Biology b, * a b
Department of Physiology, University of Toronto, Toronto, Canada Department of Biology, York University, Toronto, ON M3J 1P3, Canada
Keywords: adiponectin skeletal muscle receptors signaling metabolism autocrine endocrine myokine adiponectin resistance therapeutic
The beneficial metabolic effects of adiponectin which confer insulin-sensitizing and anti-diabetic effects are well established. Skeletal muscle is an important target tissue for adiponectin where it regulates glucose and fatty acid metabolism directly and via insulin sensitizing effects. Cell surface receptors and the intracellular signaling events via which adiponectin orchestrates metabolism are now becoming well characterized. The initially accepted dogma of adiponectin action was that the physiological effects were mediated via endocrine effects of adipose-derived adiponectin. However, in recent years it has been established that skeletal muscle can also produce and secrete adiponectin that can elicit important functional effects. There is evidence that skeletal muscle adiponectin resistance may develop in obesity and play a role in the pathogenesis of diabetes. In summary, adiponectin acting in an autocrine and endocrine manner has important metabolic and insulin sensitizing effects on skeletal muscle which contribute to the overall anti-diabetic outcome of adiponectin action. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The prevalence of obesity and diabetes has grown to epidemic proportions over the past thirty years, principally as a consequence of prolonged high carbohydrate- and high fat- containing diet in combination with decreased physical activity, and with this an alarming increase in the incidence of type 2 diabetes has emerged [1]. Research efforts to discover the various potential mechanisms linking
* Corresponding author. Tel.: þ1 416 736 2100; Fax: þ1 416 736 5698. E-mail address: [email protected] (G. Sweeney). 1521-690X/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2013.08.003
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obesity with diabetes have proliferated exponentially and we now have a solid understanding of many underlying pathophysiological events. In particular, the focus on various adipose-derived factors has yielded intriguing findings and in this article we focus on adiponectin. Notably, publications over the last two decades have documented numerous beneficial effects of adiponectin, including anti-diabetic, anti-inflammatory and cardioprotective outcomes [2–5]. This has generated great interest in understanding the precise mechanisms of adiponectin action and identifying opportunities for therapeutic exploitation [5–7]. Adiponectin is somewhat unique amongst adipokines in that despite the increasing mass of adipose tissue in the obese population, a decreased circulating level of adiponectin was observed and correlated strongly with various features of the metabolic syndrome [4,5]. Adiponectin circulates abundantly (w2–20 ug/ml) as a combination of different oligomeric forms, which include the low molecular weight (LMW, trimeric) form, the albumin binding LMW form, the medium molecular weight (MMW, hexameric) form and the high molecular weight (HMW, oligomeric) form. The mixture of these oligomeric forms is often referred to as full length adiponectin (fAd). An additional form, globular adiponectin (gAd), which contains only the C-terminal globular domain of adiponectin can also mediate biological effects. gAd can be generated by enzymatic cleavage of adiponectin, which can be mediated by leukocyte-derived elastase [8]. Hence, it is speculated that gAd generation may be most prominent at sites of inflammation. In this review we focus on the importance of skeletal muscle in adiponectin action with an emphasis on current perspectives and pertinent research questions. Metabolic effects of adiponectin in skeletal muscle It is apparent that adiponectin has widespread beneficial metabolic effects and the majority of studies have emphasized the importance of hepatic actions of adiponectin [4,5]. Importantly, many studies have clearly demonstrated that skeletal muscle is an important peripheral target tissue for adiponectin to exert its beneficial metabolic effects and contribute to anti-diabetic action. Early work in cultured mouse or rat skeletal muscle cells found that adiponectin increased glucose uptake and regulated the subsequent metabolic fate [9–13]. Similar findings were made in primary human skeletal muscle cells [14] and muscle strips from human patients [15]. We recently performed an unbiased metabolomic profiling approach to determine the metabolic changes occurring in skeletal muscle from adiponectin knockout mice fed a high fat diet, then treated with or without adiponectin [16]. It is believed that understanding changes in metabolite profiles will serve several purposes, including conferring an improved understanding of the primary mechanisms resulting in metabolic dysfunction and identifying potential opportunities for better biomarker detection [17]. Data demonstrated that the majority of high fat diet-induced changes in metabolite profiles from multiple metabolic pathways were normalized upon adiponectin supplementation [16]. The receptors and downstream signalling events via which adiponectin regulates glucose uptake in muscle have been characterized (Fig. 1). Briefly, adiponectin receptor 1 (AdipoR1) and AdipoR2 appear to be the main adiponectin receptor isoforms involved [4,5,18] although T-cadherin may have a role in binding adiponectin and facilitating signaling in skeletal muscle [19,20]. The adaptor protein containing pleckstrin homology domain, phosphotyrosin binding (PTB) domain and leucine zipper motif (APPL1) is the first and thus far best characterized adaptor protein which binds to adiponectin receptors [21,22]. Adiponectin stimulates glucose uptake in muscle via causing translocation of the glucose transporter GLUT4 to the cell surface [9] and this effect was abolished upon knockdown of APPL1 using siRNA [22]. An important downstream target of AdipoR/APPL1 signaling is AMPK which mediated many biological effects of adiponectin [4,5]. In addition to directly stimulating glucose uptake and metabolism, adiponectin enhances insulin sensitivity in muscle [23]. A potential mechanism for crosstalk between adiponectin and insulin signalling is the adiponectinmediated inhibition of p70 S6 kinase mediated serine phosphorylation of IRS1 at Ser302 and Ser636/639 via LKB1/AMPK/tuberous sclerosis 1/2 (TSC1/2) signalling [24]. The ability of adiponectin to enhance insulin stimulated phosphorylation of Akt was attenuated upon overexpression of dominant negative AMPK [24]. Studies in mouse models have further investigated the role of AdipoRs and other components of the adiponectin signalling pathway in regulating peripheral glucose homeostasis. For example, initial characterization of adiponectin knockout mice produced Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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independently by several groups showed a relatively normal phenotype with only mild or moderate insulin resistance, until challenged with high fat diet when knockout mice developed exaggerated metabolic dysfunction [25–27]. Simultaneous deletion of both AdipoR1 and R2 prevented adiponectin binding and correlated with increased triglyceride content in various tissues, development of insulin resistance, hyperinsulinemia and marked glucose intolerance [28]. AdipoR1 KO mice showed decreased glucose tolerance associated with defects in AMPK activation [28,29] whereas AdipoR2 KO mice were found in one study to have better glucose tolerance and lipid profiles compared with control mice [29]. However, upon prolonged high-fat feeding, pancreatic beta-cell failure ensued and glucose homeostasis deteriorated. Skeletal muscle specific deletion of AdipoR1, as expected, decreased glucose disposal rate [30]. Electrotransfer-mediated overexpression of APPL1 in rat skeletal muscle resulted in enhanced insulin-stimulated glucose disposal [31]. Crosstalk with not only insulin signaling but also other adipokines may be an underappreciated regulatory step in adiponectin action. Co-culture studies conducted by using primary rat adipocytes and rat skeletal muscle cells confirmed the importance of adiponectin in the regulation of glucose uptake in skeletal muscle cells [32,33]. Co-culture with primary rat adipocytes elevated glucose uptake by skeletal muscle and this response was blunted upon antibody-mediated neutralization of adiponectin or knockdown of AdipoR2 in muscle cells. Notably, adiponectin in this co-culture environment was more potent than recombinant fAd in eliciting glucose uptake, suggesting that the more physiological co-culture environment facilitated adiponectin action [33]. Furthermore, the adipokine profile secreted by primary rat adipocytes form diabetic rats contained less HMW adiponectin and correlated with less glucose uptake in muscle [32]. Thus, the ultimate functional effect of adiponectin on skeletal muscle appears to be highly dependent upon the existing intra- and extra-cellular environment at any given time. Adiponectin also regulates fatty acid metabolism in muscle and has been shown to increase fatty acid uptake and oxidation and suppress fatty acid synthesis through the activation of AMPK, p38 MAPK and PPARa [10,11,34,35]. Adiponectin’s ability to up-regulate fatty acid oxidation is supported by gain/loss of function studies where overexpression/knockdown of AdipoRs showed an enhanced/ suppressed fatty acid oxidation, with correlative changes in respective signaling pathways in myocytes [18]. In addition to direct effects on substrate metabolism, adiponectin can also improve mitochondrial bioenergetics, including induction of skeletal muscle biogenesis [30,36,37]. Adiponectin can induce a fiber type switch to provide more oxidative capacity through an AMPK-myocyte enhancer factor 2C (MEF2C)-PGC1a pathway [36]. Indeed, the potential for adiponectin to control myogenesis by regulating proliferation, differentiation and fusion of skeletal muscle precursors, and even dictating muscle fiber type profiles, now appears to be an important functional consequence of adiponectin action with potential significance in several disease states where muscle regeneration is needed [30,38–42]. Interestingly, numerous studies have shown a correlation between gender and adiponectin action. Male individuals typically have lower levels of circulating oligomeric adiponectin forms compared to female individuals due to an interaction between adiponectin and the sex hormone testosterone [43]. There were strong inverse associations between circulating HMW adiponectin and intramyocellular lipid content measured using proton magnetic resonance spectroscopy in human skeletal muscle [44]. Serum adiponectin was positively associated with AMPK phosphorylation and glucose uptake and negatively associated with ceramide content in skeletal muscle of healthy, young, lean men, but not in women [42]. Furthermore, women had lower AdipoR1 expression in skeletal muscle and a lower percentage of type 2 glycolytic muscle fibers than men [42]. The sex-dependent changes in adiponectin levels and action have now been highlighted in several studies and should perhaps be borne in mind as an important consideration in future studies. Adiponectin as an adipokine and myokine The physiological significance of adipokines is well established and, in an analogous fashion, we now appreciate that a similar phenomenon exists with respect to skeletal muscle [45]. Indeed, numerous proteomics-driven studies have recently begun to characterize the muscle secretome (or myokinome) and the changes which occur under pathophysiological conditions, or in vitro conditions Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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mimicking these [45,46]. Although adipocytes are the principal source of circulating adiponectin, several studies have now uncovered the potential for adiponectin production by skeletal muscle and other cell types [23,41,47–51]. To address the potential significance of adiponectin as a myokine, initial experiments set out to examine adiponectin expression in skeletal muscle, determine the changes in adiponectin expression in skeletal muscle from obese/diabetic animal models and to use gain or loss of function approaches to determine the functional significance. Adiponectin messenger RNA and protein was observed in mouse skeletal muscles and cultured skeletal muscle cell lines [41]. There was a relationship between adiponectin expression and fiber type or intramyocellular lipid. Adiponectin expression was highest in type IIA or IID fibers and the majority of fibers with high adiponectin levels also showed elevated intramyocellular lipid [41]. Notably, muscle-derived adiponectin was shown to correlate with muscle function. Upon in situ muscle stimulation, lower peak tetanic forces were detected in adiponectin knockout mice relative to wild type. No change was observed in low-frequency fatigue rates [41]. Thiazolidinediones are well known to mediate anti-diabetic effects at least in part by stimulating adiponectin production by adipocytes. Rosiglitazone has now also been shown to elevate adiponectin synthesis and secretion by skeletal muscle cells and this directly correlated with direct activation of adiponectin signaling and rosiglitazone-mediated improvement in insulin sensitivity [23,47]. Furthermore, rosiglitazone treatment also attenuated the reduced skeletal muscle adiponectin levels observed in high-fat high-sucrose fed rats [23]. Genetic manipulation to produce transgenic mice with enhanced PPAR-gamma activity in skeletal muscle also increased adiponectin expression in this tissue and conferred protection from high fat diet-induced insulin resistance [47]. Further direct evidence of the functional significance of adiponectin production in skeletal muscle in regulation of metabolism was provided by studies in which skeletal muscle cells were engineered to overexpress the adiponectin gene. These cells synthesized and secreted more adiponectin than control cells which directly induced glucose uptake and increased insulin sensitivity [23]. The same phenomena was observed in a mouse model in which the adiponectin gene was specifically overexpressed in skeletal muscle using ultrasound targeted microbubble delivery. Adiponectin overexpression in skeletal muscle increased insulin sensitivity in this tissue and attenuated high fat diet-induced defects in peripheral glucose homeostasis [52]. Study of muscle from adiponectin knockout mice found evidence of enhanced oxidative stress, lipid peroxidation and apoptosis and these abnormalities could be corrected by electrotransfer-mediated restoration of adiponectin expression in the muscle [50]. Hence, it is now clear that adiponectin is produced by skeletal muscle, and its level changes in disease states. The muscle-derived adiponectin not only has important autocrine and/or paracrine effects but may also elicit endocrine effects in other target tissues, such as liver. Adiponectin resistance The development of insulin resistance in skeletal muscle is well accepted as a major contributor to type 2 diabetes. The concept of adiponectin resistance has been mooted and there is strong likelihood that it has important significance in certain pathologies. For example, adiponectin’s metabolic effects in human skeletal muscle were blunted in tissue from obese individuals and feeding a diet high in saturated fats attenuated adiponectin-stimulated signalling and fatty acid metabolism in rodent skeletal muscle [53–55]. It has been proposed that adiponectin resistance precedes lipid accumulation and further metabolic disturbances induced by lipotoxicity [56]. There are several potential mechanisms which may lead to adiponectin resistance, for example reduced expression of one or more adiponectin receptors. Insulin may be an important regulator of adiponectin sensitivity since insulin administration reduced AdipoR expression in several tissues of streptozotocin-induced diabetic mice [57]. Insulin also decreased AdipoR1 levels in cultured skeletal muscle cells, although contrasting effects have been reported on AdipoR2 [57,58]. Interestingly, high glucose conditions were also found to reduce AdipoR1 and AdipoR2 expression in L6 cells [58]. Skeletal muscle AdipoR levels were reduced in ob/ob mice and this led to decreased adiponectin binding to skeletal muscle membrane fractions and functional adiponectin resistance. When adiponectin resistance occurs in the face of normal AdipoR expression, altered expression or posttranslational modification of signalling intermediates in skeletal muscle may also dictate cellular sensitivity to adiponectin [14,21,59,60]. This question should be more rigorously tested in the near future. The regulation of AdipoRs has been recently reviewed [61] and it is Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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intriguing to note that exercise increased expression of APPL1 [62,63], an effect which may at least in part explain the resultant beneficial metabolic effects [64]. Nevertheless, another study showed that chronic exercise training did not improve high fat diet-induced adiponectin resistance in rats [53]. APPL1 expression and phosphorylation on Ser401 was found to be enhanced in obese individuals with type 2 diabetes, perhaps as part of a compensatory mechanism, and levels were reduced after bariatric surgery [65]. It is generally accepted that effects of adiponectin on skeletal muscle mitochondria contribute to improved metabolism. However, somewhat unexpectedly, a study in which muscle biopsies from diabetic patients were treated with adiponectin indicated no significant change in skeletal muscle mitochondrial bioenergetics and adiponectin resistance was proposed as a potential explanation [66]. Although adipocytes and myocytes are often the focus of inter-organ crosstalk, some recent evidence suggests that cardiac and skeletal muscle interactions may have been much underappreciated [67]. A study of skeletal muscle biopsies from patients with chronic heart failure or healthy individuals showed that muscle of the former group had 5-fold elevated muscle adiponectin mRNA levels but significantly reduced AdipoR1 expression, again suggesting the possible existence of adiponectin resistance [51]. Overall, there is evidence that adiponectin resistance occurs in skeletal muscle under certain pathological conditions although the contribution of adiponectin resistance versus adiponectin deficiency towards diabetes needs to be more thoroughly investigated. Potential therapeutic applications of targeting adiponectin action in skeletal muscle The well documented widespread beneficial physiological actions of adiponectin spanning diabetes, inflammation, cardiovascular diseases and cancer have provided much impetus for discovery and development of adiponectin-based therapeutics [68]. Since synthesis and administration of recombinant forms of adiponectin has not proven to be a viable therapeutic approach, largely due to the cost of synthesizing correctly posttranslationally modified bioactive forms, there is a clear need for discovery of compounds which mimic or enhance adiponectin action. There have been reports of several adiponectin-mimetic small molecules at various stages of the drug discovery pipeline, however specific adiponectin-like or adiponectin-sensitizing therapeutics are not yet available. Interestingly, a variety of patents pertaining to adiponectin now exist and one recent addition describes an agent for oral administration comprising adiponectin as an active ingredient (patent publication number: US 2012/ 0115776 A1). It should also be pointed out that several existing drugs, notably thiazolidinediones, and various natural compounds such as dietary fish oils, osmotin and resveratrol can all act at least in part by enhancing adiponectin levels [69,70]. For example, fish oil-derived n-3 polyunsaturated fatty acids prevented defects in adiponectin action in soleus muscle that had been induced by feeding a diet rich in saturated fats [71]. With regard to skeletal muscle, the tissue content of adiponectin was increased by thiazolidinedione treatment in rats [23] and the ultrasound targeted microbubble delivery of adiponectin gene to overexpress specifically in skeletal muscle conveyed anti-diabetic effects [52]. Thus, a potentially promising therapeutic approach may be targeting the myokine properties of adiponectin. This may be achieved with the continued development of therapeutic approaches to specifically target genes or compounds to skeletal muscle [72–74]. Summary The anti-diabetic effects of adiponectin are well characterized and regulation of skeletal muscle metabolism is an important contributory mechanism. The AdipoR isoforms and APPL1-dependent downstream signalling events play a vital role in adiponectin’s metabolic effects in muscle. When circulating adiponectin levels fall or skeletal muscle becomes resistant to adiponectin action the lack of proper glucose and fatty acid homeostasis in muscle contributes to the development of diabetes. An interesting facet to emerge in recent years is that adiponectin is also a myokine, being produced and released by skeletal muscle and mediating functional effects on insulin sensitivity, metabolism and myogenesis. The clinical significance of our current understanding of adiponectin biology is two-fold; first, because adiponectin can be regarded as a robust biomarker for identifying individuals with metabolic syndrome and secondly because adiponectin is an attractive therapeutic target. Please cite this article in press as: Liu Y, Sweeney G, Adiponectin action in skeletal muscle, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/j.beem.2013.08.003
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Fig. 1. Schematic representation depicting regulation of energy metabolism by adiponectin in skeletal muscle Adiponectin exerts its beneficial effect on the regulation of skeletal muscle energy metabolism by various mechanisms, including increasing basal and insulin stimulated glucose uptake via GLUT4 translocation and fatty acid uptake and oxidation directly or indirectly through mitochondrial biogenesis. The increased rate of lipid and glucose clearance due to adiponectin will also eventually lead to enhanced insulin sensitivity via the combination of effects resulting from decreased inflammation, decreased ROS production and improved mitochondrial function. ROS: reactive oxygen species; IRS1/2: insulin receptor substrate 1/2; Akt: protein kinase B; PI3K: phosphatidylinositol 3 kinase; PDK1: 3-phosphoinositide-dependent protein kinase 1; mTOR: mammalian target of rapamycin; S6K: p70 S6 kinase; Rheb: Ras homolog enriched in brain; TSC1/2: tuberous sclerosis complex; LKB1: liver kinase B1; Rab5: Ras in the brain 5; CaMKKb: Ca2þ/calmodulin dependent protein kinase kinase beta; PGC1a: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Sirt1: silent mating type information regulation 2 homolog 1; PPARa: peroxisome proliferator-activated receptor alpha; Acox: acyl-CoA oxidase 1; Ucp2: uncoupling protein 2.
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Practice points Despite significant improvements in the arsenal with which diabetes can be treated there are still significant unmet needs. Lessons learned from clinical studies, animal models and molecular studies suggest, for the most part, that adiponectin mediates anti-diabetic effects. Thus, it would be advantageous to develop approaches to increase adiponectin levels or enhance adiponectin action for the treatment of diabetes. Use of adiponectin based therapeutics may become reality in the near future. Adiponectin, in particular the HMW form, can be considered as a robust biomarker for metabolic syndrome.
Research agenda Further studies are needed to clarify the functional significance of adiponectin produced by skeletal muscle. We must understand if the local pool of adiponectin acts in the same way or in a different manner compared with the circulating pool of adiponectin. Does generation of globular adiponectin represent a physiologically significant regulatory step in adiponectin action? We should investigate when and how adiponectin resistance occurs and if it is tissue specific. Drug discovery programs should be designed to identify small molecules that enhance or mimic adiponectin action.
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