Differential Expression of Novel Adiponectin Receptor-1 Transcripts in Skeletal Muscle of Subjects With Normal Glucose Tolerance and Type 2 Diabetes

OBJECTIVE Adiponectin receptor-1 (AdipoR1) expression in skeletal muscle has been suggested to play an important role in insulin resistance and diabetes. We aimed at evaluating the presence of novel AdiopR1 splice variants in human muscle and their regulation under physiological and pathophysiological states. RESEARCH DESIGN AND METHODS AdipoR1 5′UTR mRNA transcripts, predicted from bioinformatics data, were evaluated in fetal and adult human tissues. Expression and function of the identified transcripts were assessed in cultured human skeletal muscle cells and in muscle biopsies obtained from individuals with normal glucose tolerance (NGT) and type 2 diabetes (n = 49). RESULTS Screening of potential AdipoR1 5′UTR splice variants revealed a novel highly abundant muscle transcript (R1T3) in addition to the previously described transcript (R1T1). Unlike R1T1, R1T3 expression was significantly increased during fetal development and myogenesis, paralleled with increased AdipoR1 protein expression. The 5′UTR of R1T3 was found to contain upstream open reading frames that repress translation of downstream coding sequences. Conversely, AdipoR1 3′UTR was associated with enhanced translation efficiency during myoblast-myotube differentiation. A marked reduction in muscle expression of R1T3, R1T1, and R1T3-to-R1T1 ratio was observed in individuals with type 2 diabetes compared with expression levels of NGT subjects, paralleled with decreased expression of the differentiation marker myogenin. Among NGT subjects, R1T3 expression was positively correlated with insulin sensitivity. CONCLUSIONS These results indicate that AdipoR1 receptor expression in human skeletal muscle is subjected to posttranscriptional regulation, including alternative splicing and translational control. These mechanisms play an important role during myogenesis and may be important for whole-body insulin sensitivity.

[1]  Philippe Froguel,et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects , 2003, Nature.

[2]  Guirong Wang,et al.  Differences in the translation efficiency and mRNA stability mediated by 5'-UTR splice variants of human SP-A1 and SP-A2 genes. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[3]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[4]  W. Gish,et al.  Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. , 2001, Genome research.

[5]  S. Kihara,et al.  Adiponectin Stimulates Angiogenesis in Response to Tissue Ischemia through Stimulation of AMP-activated Protein Kinase Signaling* , 2004, Journal of Biological Chemistry.

[6]  F. Toledo,et al.  Insulin Resistance Is Associated With Higher Intramyocellular Triglycerides in Type I but Not Type II Myocytes Concomitant With Higher Ceramide Content , 2009, Diabetes.

[7]  O. Elroy-Stein,et al.  Translational Control of Protein Kinase Cη by Two Upstream Open Reading Frames , 2009, Molecular and Cellular Biology.

[8]  Zhenzhen Wang,et al.  Negative regulation of adiponectin receptor 1 promoter by insulin via a repressive nuclear inhibitory protein element , 2008, FEBS letters.

[9]  S. O’Rahilly,et al.  Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. , 2002, Endocrinology.

[10]  Andrew J. Olson,et al.  Computational analysis of alternative splicing using EST tissue information. , 2002, Genomics.

[11]  V. Mootha,et al.  Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans , 2009, Proceedings of the National Academy of Sciences.

[12]  G. Sweeney,et al.  Circulating adiponectin and adiponectin receptor expression in skeletal muscle: effects of exercise , 2007, Diabetes/metabolism research and reviews.

[13]  B. Kemp,et al.  Differential Regulation of Adiponectin Receptor Gene Expression by Adiponectin and Leptin in Myotubes Derived from Obese and Diabetic Individuals , 2006, Obesity.

[14]  Kohjiro Ueki,et al.  Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. , 2006, The Journal of clinical investigation.

[15]  R. Paschke,et al.  Altered fiber distribution and fiber-specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes. , 2006, Diabetes care.

[16]  Y. Hayashi,et al.  Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 , 2010, Nature.

[17]  T. Ciaraldi,et al.  Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults. , 2007, American journal of physiology. Endocrinology and metabolism.

[18]  G. Gerlitz,et al.  Phosphorylation of initiation factor-2 alpha is required for activation of internal translation initiation during cell differentiation. , 2002, European Journal of Biochemistry.

[19]  D. Morris,et al.  Upstream Open Reading Frames as Regulators of mRNA Translation , 2000, Molecular and Cellular Biology.

[20]  Christopher J. Lee,et al.  Genome-wide detection of alternative splicing in expressed sequences of human genes , 2001, Nucleic Acids Res..

[21]  M. Kjaer,et al.  Gene expression of myogenic factors and phenotype-specific markers in electrically stimulated muscle of paraplegics. , 2005, Journal of applied physiology.

[22]  Kohjiro Ueki,et al.  Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. , 2007, Cell metabolism.

[23]  P. O’Shaughnessy,et al.  Identification of a novel melanocortin 2 receptor splice variant in murine adipocytes: implications for post-transcriptional control of expression during adipogenesis. , 2006, Journal of molecular endocrinology.

[24]  P. Scherer,et al.  The adipocyte-secreted protein Acrp30 enhances hepatic insulin action , 2001, Nature Medicine.

[25]  C. Mantzoros,et al.  Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training. , 2006, The Journal of clinical endocrinology and metabolism.

[26]  G. Heigenhauser,et al.  The stimulatory effect of globular adiponectin on insulin-stimulated glucose uptake and fatty acid oxidation is impaired in skeletal muscle from obese subjects. , 2005, Diabetes.

[27]  A. Hamsten,et al.  Alternative splicing of human peroxisome proliferator-activated receptor delta (PPARdelta):effects on translation efficiency and trans-activation ability , 2007, BMC Molecular Biology.

[28]  Z. Madar,et al.  A High‐Fat Diet Has a Tissue‐Specific Effect on Adiponectin and Related Enzyme Expression , 2006, Obesity.

[29]  T. Funahashi,et al.  Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy , 2005, Diabetologia.

[30]  Juei-Tang Cheng,et al.  Increase of adiponectin receptor gene expression by physical exercise in soleus muscle of obese Zucker rats , 2006, European Journal of Applied Physiology.

[31]  J. Eckel,et al.  Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility. , 2008, American journal of physiology. Endocrinology and metabolism.

[32]  B. Kemp,et al.  Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics. , 2005, The Journal of clinical endocrinology and metabolism.

[33]  P. Froguel,et al.  Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity* , 2004, Journal of Biological Chemistry.

[34]  H. Sone,et al.  The effect of exercise training on adiponectin receptor expression in KKAy obese/diabetic mice. , 2006, The Journal of endocrinology.

[35]  J. Pal,et al.  Role of 5′‐ and 3′‐untranslated regions of mRNAs in human diseases , 2009, Biology of the cell.

[36]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[37]  Hua V. Lin,et al.  Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice , 2007, Diabetes.

[38]  W. Inder,et al.  Adiponectin, skeletal muscle adiponectin receptor expression and insulin resistance following dexamethasone , 2008, Clinical endocrinology.

[39]  T. Funahashi,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resistance , 2022 .

[40]  A. Colling-Saltin.  Enzyme histochemistry on skeletal muscle of the human foetus , 1978, Journal of the Neurological Sciences.

[41]  H. Vidal,et al.  Changes in adiponectin, its receptors and AMPK activity in tissues of diet-induced diabetic mice. , 2008, Diabetes & metabolism.

[42]  E. Ravussin,et al.  Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes , 2004, Diabetologia.

[43]  S. O’Rahilly,et al.  Induction of Adipocyte Complement-related Protein of 30 Kilodaltons by Ppar␥ Agonists: a Potential Mechanism of Insulin Sensitization , 2022 .

[44]  H. Koistinen,et al.  Globular adiponectin stimulates glucose transport in type 2 diabetic muscle , 2008, Diabetes/metabolism research and reviews.

[45]  M. Matsuda,et al.  PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. , 2001, Diabetes.

[46]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[47]  M. Prentki,et al.  Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial , 2009, Diabetologia.

[48]  T Nakamura,et al.  Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[49]  H. Meijer,et al.  Control of eukaryotic protein synthesis by upstream open reading frames in the 5'-untranslated region of an mRNA. , 2002, The Biochemical journal.

[50]  K. Inukai,et al.  Regulation of adiponectin receptor gene expression in diabetic mice. , 2005, American journal of physiology. Endocrinology and metabolism.