Downregulation of adiponectin expression by IL-6 & Functional analyses of novel genetic variants of DGAT1 and DGAT2 in humans

Abstract

Obesity is characterized by two major events: systemic low-grade inflammation and energy metabolism imbalance. Adiponectin, an adipocyte-derived protein, has insulin-sensitizing properties in muscle and liver. Its expression and plasma concentrations are decreased in obesity. Our studies examined the role of interleukin-6 (IL-6), an important obesity-related cytokine, on adiponectin gene expression. IL-6 decreased adiponectin expression in a time- and dose-dependent manner in both human primary adipocytes and 3T3-L1 cells through a p44/42 MAP kinase-dependent pathway. In vivo studies demonstrated that IL-6 KO mice have increased plasma adiponectin levels on both a chow and a high fat/high glucose diet. Acyl-CoA: diacylglycerol acyltransferase (DGAT) is a key enzyme in triglyceride biosynthesis. Although many studies have demonstrated the role of DGAT in rodents, very little is known about its role in humans. Our studies identified a novel stop codon in the DGAT2 gene, which results in decreased DGAT2 mRNA expression in adipocytes and is associated with decreased triglyceride levels.