Adiponectin action in skeletal muscle
01 Jan 2014-Best Practice & Research Clinical Endocrinology & Metabolism (Best Pract Res Clin Endocrinol Metab)-Vol. 28, Iss: 1, pp 33-41
TL;DR: 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.
About: This article is published in Best Practice & Research Clinical Endocrinology & Metabolism.The article was published on 2014-01-01. It has received 88 citations till now. The article focuses on the topics: Adiponectin & Skeletal muscle.
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TL;DR: The understanding of this system will enable to define new levers to prevent/treat sarcopenia and osteoporosis at the same time, which might include nutritional interventions and physical exercise.
247 citations
Cites background from "Adiponectin action in skeletal musc..."
...Adiponectin has a metabolic protective effect on skeletal muscle, as it promotes glucose and fatty acids homeostasis (Liu and Sweeney, 2014) while adiponectin deficiency leads to insulin resistance (Karpe, 2013)....
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TL;DR: The current roles of adiponectin in metabolic disorders and autoimmune diseases is summarized and knowledge on the specific functions of isoforms would help develop potential anti-inflammatory therapeutics to target specific adiponECTin isoforms against metabolic disordersand autoimmune diseases.
Abstract: Adiponectin is the richest adipokine in human plasma, and it is mainly secreted from white adipose tissue. Adiponectin circulates in blood as high-molecular, middle-molecular, and low-molecular weight isoforms. Numerous studies have demonstrated its insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects. Additionally, decreased serum levels of adiponectin is associated with chronic inflammation of metabolic disorders including Type 2 diabetes, obesity, and atherosclerosis. However, recent studies showed that adiponectin could have pro-inflammatory roles in patients with autoimmune diseases. In particular, its high serum level was positively associated with inflammation severity and pathological progression in rheumatoid arthritis, chronic kidney disease, and inflammatory bowel disease. Thus, adiponectin seems to have both pro-inflammatory and anti-inflammatory effects. This indirectly indicates that adiponectin has different physiological roles according to an isoform and effector tissue. Knowledge on the specific functions of isoforms would help develop potential anti-inflammatory therapeutics to target specific adiponectin isoforms against metabolic disorders and autoimmune diseases. This review summarizes the current roles of adiponectin in metabolic disorders and autoimmune diseases.
176 citations
Cites background from "Adiponectin action in skeletal musc..."
...In addition, adipose tissue plays an indispensable role in lipid obilization and energy distribution in the body [48]....
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...In addition, adipose tissue plays an indispensable role in lipid mobilization and energy distribution in the body [48]....
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TL;DR: In summary, adiponectin stimulated skeletal muscle autophagy and antioxidant potential to reduce insulin resistance caused by HFD and overexpressed an inactive mutant of Atg5 to create an Autophagy-deficient cell model, and together with pharmacological inhibition of autphagy, demonstrated reduced insulin sensitivity under these conditions.
Abstract: Numerous studies have characterized the antidiabetic effects of adiponectin, yet the precise cellular mechanisms in skeletal muscle, in particular, changes in autophagy, require further clarification. In the current study, we used a high-fat diet (HFD) to induce obesity and insulin resistance in wild-type (WT) or adiponectin knockout (Ad-KO) mice with and without adiponectin replenishment. Temporal analysis of glucose tolerance and insulin sensitivity using hyperinsulinemic-euglycemic clamp and muscle insulin receptor substrate and Akt phosphorylation demonstrated exaggerated and more rapid HFD-induced insulin resistance in skeletal muscle of Ad-KO mice. Superoxide dismutase activity, the reduced glutathione-to-glutathione disulfide ratio, and lipid peroxidation indicated that HFD-induced oxidative stress was corrected by adiponectin. Gene array analysis implicated several antioxidant enzymes, including Gpxs, Prdx, Sod, and Nox4, in mediating this effect. Adiponectin also attenuated palmitate-induced reactive oxygen species production in cultured myotubes and improved insulin-stimulated glucose uptake in primary muscle cells. Increased LC3-II and decreased p62 expression suggested that HFD induced autophagy in muscle of WT mice; however, these changes were not observed in Ad-KO mice. Replenishing adiponectin in Ad-KO mice increased LC3-II and Beclin1 and decreased p62 protein levels, induced fibroblast growth factor-21 expression, and corrected HFD-induced decreases in LC3, Beclin1, and ULK1 gene expression. In vitro studies examining changes in phospho-ULK1 (Ser555), LC3-II, and lysosomal enzyme activity confirmed that adiponectin directly induced autophagic flux in cultured muscle cells in an AMPK-dependent manner. We overexpressed an inactive mutant of Atg5 to create an autophagy-deficient cell model, and together with pharmacological inhibition of autophagy, demonstrated reduced insulin sensitivity under these conditions. In summary, adiponectin stimulated skeletal muscle autophagy and antioxidant potential to reduce insulin resistance caused by HFD.
175 citations
Cites background from "Adiponectin action in skeletal musc..."
...Numerous studies have demonstrated that adiponectin improves insulin sensitivity and alleviates metabolic dysfunction in skeletal muscle (2,19)....
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TL;DR: This review proposes and emphasizes that increased expression of the C- terminal agrin fragment (CAF) associated with age-dependent neuromuscular junction (NMJ) dysfunction, as well as skeletal muscle-specific troponin T (sTnT), a key component of contractile machinery, are the emerging sarcopenia biomarkers.
136 citations
Cites background from "Adiponectin action in skeletal musc..."
..., 2015), and adiponectin (Liu and Sweeney, 2014) have been proposed as muscle growth factors, and therefore, as all potential sarcopenia biomarkers....
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...…et al., 2014), caveolin-3 (Hadj Sassi et al., 2012), follistatin-like protein 1 (FSTL1) (Görgens et al., 2013), perilipins 2 and 5 (Conte et al., 2015), and adiponectin (Liu and Sweeney, 2014) have been proposed as muscle growth factors, and therefore, as all potential sarcopenia biomarkers....
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TL;DR: New insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors are provided and will support the development of adipOSE- derived factors as potential therapeutic targets for obesity and T2DM.
Abstract: Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues—the white adipose tissue (WAT) and brown adipose tissue (BAT)—secrete bioactive peptides and proteins, known as “adipokines” and “batokines,” respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, “exosomal microRNAs (miRNAs)” were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors—adipokines, batokines, and exosomal miRNA—in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.
107 citations
Cites background from "Adiponectin action in skeletal musc..."
...Skeletal muscles can also generate and secrete adiponectin [48]....
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References
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TL;DR: It is shown that phosphorylation and activation of the 5′-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full- lengths Ad in the liver, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK.
Abstract: Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
4,298 citations
TL;DR: The cloning of complementary DNAs encoding adiponectin receptors 1 and 2 by expression cloning supports the conclusion that they serve as receptors for globular and full-length adiponECTin, and that they mediate increased AMP kinase and PPAR-α ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectionin.
Abstract: Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
3,013 citations
TL;DR: The results indicate that adiponectin/ACRP30 deficiency and high TNF-α levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
Abstract: Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
2,095 citations
TL;DR: The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain.
Abstract: During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
2,002 citations
TL;DR: Daily administration of a very low dose of gAcrp30 to mice consuming a high-fat/sucrose diet caused profound and sustainable weight reduction without affecting food intake.
Abstract: Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe novel pharmacological properties of the protease-generated globular head domain of Acrp30 (gAcrp30). Acute treatment of mice with gAcrp30 significantly decreased the elevated levels of plasma free fatty acids caused either by administration of a high fat test meal or by i.v. injection of Intralipid. This effect of gAcrp30 was caused, at least in part, by an acute increase in fatty acid oxidation by muscle. As a result, daily administration of a very low dose of gAcrp30 to mice consuming a high-fat/sucrose diet caused profound and sustainable weight reduction without affecting food intake. Thus, gAcrp30 is a novel pharmacological compound that controls energy homeostasis and exerts its effect primarily at the peripheral level.
1,997 citations