Impaired Multimerization of Human Adiponectin Mutants Associated with Diabetes

By H. Waki, Toshimasa Yamauchi, J. Kamon, Yusuke Ito, Shoko Uchida, Shunbun Kita, K. Hara, Yusuke Hada, F. Vasseur, Philippe Froguel and 3 more. Journal of Biological Chemistry, 2003

1,014 citations recorded by the source corpus.

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.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/73195e6baa4f31484588cd5d4d84bb7ba4f0ad96

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cardiology and Cardiovascular Medicine

In Epidemiology

Citations in the corpus

Adipose tissue as an endocrine organ. (2010, background): “Consequently naturally occurring SNPs, such as those giving rise to the mutations Gly84Arg and Gly90Ser that impair oligomerisation through abrogation of Cys-39 disulphide-bond formation, are closely associated with insulin resistance and type 2 diabetes (Waki et al., 2003).”
Adipocytokines: mediators linking adipose tissue, inflammation and immunity (2006, background): “Both trimers and other oligomers of adiponectin are present in the circulation, whereas the presence of the globular fragment in the serum in humans has been questione”
Adiponectin and adiponectin receptors. (2005, methodology): “In addition to the relatively common SNPs, eight mutations in the human adiponectin gene have been reported (69, 74, 75), some of which were significantly related to diabetes and hypoadiponectinemia (23, 75).”
Adipocytes as regulators of energy balance and glucose homeostasis (2006, background): “Circulating adiponectin can exist as a trimer, hexamer or a higher-order multimer with 12–18 subunit”
Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation Published, JLR Papers in Press, April 16, 2005. DOI 10.1194/jlr.M400373-JLR200 (2005, background): “There is also evidence that adiponectin gene polymorphisms may be associated with hypoadiponectinemia, together with insulin resistance and type 2 diabetes (7).”