Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S et al.. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 278, 40352-40363

Institut Pasteur de Lille, Lille, Nord-Pas-de-Calais, France
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2003; 278(41):40352-63. DOI: 10.1074/jbc.M300365200
Source: PubMed


Adiponectin is an adipocyte-derived hormone, which has been shown to play important roles in the regulation of glucose and lipid metabolism. Eight mutations in human adiponectin have been reported, some of which were significantly related to diabetes and hypoadiponectinemia, but the molecular mechanisms of decreased plasma levels and impaired action of adiponectin mutants were not clarified. Adiponectin structurally belongs to the complement 1q family and is known to form a characteristic homomultimer. Herein, we demonstrated that simple SDS-PAGE under non-reducing and non-heat-denaturing conditions clearly separates multimer species of adiponectin. Adiponectin in human or mouse serum and adiponectin expressed in NIH-3T3 or Escherichia coli formed a wide range of multimers from trimers to high molecular weight (HMW) multimers. A disulfide bond through an amino-terminal cysteine was required for the formation of multimers larger than a trimer. An amino-terminal Cys-Ser mutation, which could not form multimers larger than a trimer, abrogated the effect of adiponectin on the AMP-activated protein kinase pathway in hepatocytes. Among human adiponectin mutations, G84R and G90S mutants, which are associated with diabetes and hypoadiponectinemia, did not form HMW multimers. R112C and I164T mutants, which are associated with hypoadiponectinemia, did not assemble into trimers, resulting in impaired secretion from the cell. These data suggested impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. In conclusion, not only total concentrations, but also multimer distribution should always be considered in the interpretation of plasma adiponectin levels in health as well as various disease states.

17 Reads
  • Source
    • "Genetic alterations were correlated to adiponectin expression in metabolic diseases [76]; for example, p.G48R, P.Y111H, p.R112C, and p.G90S mutations are strongly associated with low levels of total adiponectin and HMW oligomers in patients affected by T2DM and obesity [43, 45, 46, 77]. Furthermore, 12 SNPs in adiponectin gene (APM1) were identified; some of these SNPs and haplotypes are correlated to hypoadiponectinemia, IR, and increased risk of T2DM [43]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is a major health problem strongly increasing the risk for various severe related complications such as metabolic syndrome, cardiovascular diseases, respiratory disorders, diabetic retinopathy, and cancer. Adipose tissue is an endocrine organ that produces biologically active molecules defined "adipocytokines," protein hormones with pleiotropic functions involved in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, cell proliferation, and so forth. In obesity, fat accumulation causes dysregulation of adipokine production that strongly contributes to the onset of obesity-related diseases. Several advances have been made in the treatment and prevention of obesity but current medical therapies are often unsuccessful even in compliant patients. Among the adipokines, adiponectin shows protective activity in various processes such as energy metabolism, inflammation, and cell proliferation. In this review, we will focus on the current knowledge regarding the protective properties of adiponectin and its receptors, AdipoRs ("adiponectin system"), on metabolic complications in obesity and obesity-related diseases. Adiponectin, exhibiting antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important clinical benefits in terms of development of therapies for the prevention and/or for the treatment of obesity and obesity-related diseases.
    BioMed Research International 07/2014; 2014(6778):658913. DOI:10.1155/2014/658913 · 2.71 Impact Factor
  • Source
    • "Low level of adipnectin was associated with insulin resistance, obesity, and T2D [9]. Adiponectin is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin, which exists as three forms: a trimer of low molecular weight, a hexamer of medium molecular weight and a larger multimeric high molecular weight (HMW) form [10]. Glimepiride is reported to increase adiponectin gene expression in adipocytes [11]. And several studies have also demonstrated that glimepiride may increase in insulin sensitivity associated with increased serum adiponectinemia [12-14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To observe the efficacy and safety of adding glimepiride to established insulin therapy in poorly controlled type 2 diabetes (T2D) and to assess the relationship of changes in the serum high-molecular weight (HMW) adiponectin levels and glycemic control after glimepiride treatment. Fifty-six subjects with poorly controlled insulin-treated T2D were randomly assigned to either the glimepiride-added group (the group A, n = 29) or the insulin-increasing group (the group B, n = 27) while continuing current insulin-based therapy. Glycosylated hemoglobin (HbA1c) value, daily insulin dose, body weight, waist circumference, plasma lipid concentration, serum HMW adiponectin level and the number of hypoglycemic events were evaluated before and after treatment. At the end of study, insulin doses were significantly reduced, and the mean HbA1c, fasting blood glucose (FBG) and 2-hour postprandial blood glucose (P2BG) were improved greater in the group A compared with the group B. The serum HMW adiponectin levels were significantly increased in the group A compared with the group B. Most importantly, we found that changes in HbA1c were inversely correlated with changes in serum HMW adiponectin in the group A (r = -0.452, p = 0.02). Adding glimepiride to current insulin treatment led to better improvement in glycemic control with a significant smaller daily insulin dose, and the increases in the serum HMW adiponectin levels may directly contribute to improvement glycemic control.
    Diabetology and Metabolic Syndrome 03/2014; 6(1):41. DOI:10.1186/1758-5996-6-41 · 2.17 Impact Factor
  • Source
    • "Adiponectin plasma levels are inversely proportional to body mass index and visceral adiposity and can be found in the circulation as a number of multimeric complexes: low molecular weight trimers, medium molecular weight hexamers, and high molecular weight (HMW) multimers (12 to 18 mers). The HMW multimer appears to be the most active form of adiponectin, as plasma concentration of HMW multimers is related to insulin sensitivity, and failure in the multimerization of adiponectin in humans is associated with type 2 diabetes mellitus (58). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous studies address the physiology of adipose tissue (AT). The interest surrounding the physiology of AT is primarily the result of the epidemic outburst of obesity in various contemporary societies. Briefly, the two primary metabolic activities of white AT include lipogenesis and lipolysis. Throughout the last two decades, a new model of AT physiology has emerged. Although AT was considered to be primarily an abundant energy source, it is currently considered to be a prolific producer of biologically active substances, and, consequently, is now recognized as an endocrine organ. In addition to leptin, other biologically active substances secreted by AT, generally classified as cytokines, include adiponectin, interleukin-6, tumor necrosis factor-alpha, resistin, vaspin, visfatin, and many others now collectively referred to as adipokines. The secretion of such biologically active substances by AT indicates its importance as a metabolic regulator. Cell turnover of AT has also recently been investigated in terms of its biological role in adipogenesis. Consequently, the objective of this review is to provide a comprehensive critical review of the current literature concerning the metabolic (lipolysis, lipogenesis) and endocrine actions of AT.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 03/2014; 47(3):192-205. DOI:10.1590/1414-431X20132911 · 1.01 Impact Factor
Show more