Hypoxia-inducible factor 1? regulates a SOCS3-STAT3-adiponectin signal transduction pathway in adipocytes.

ABSTRACT: Obesity has been identified as a major risk factor for type 2 diabetes, characterized by insulin resistance in insulin target tissues. Hypoxia-inducible factor 1? (HIF1?) regulates pathways in energy metabolism that become dysregulated in obesity. Earlier studies revealed that HIF1? in adipose tissue is markedly elevated in high-fat diet-fed mice that are obese and insulin-resistant. Genetic ablation of HIF1? in adipose tissue decreased insulin resistance and obesity, accompanied by increased serum adiponectin levels. However, the exact mechanism whereby HIF1? regulates adiponectin remains unclear. Here, acriflavine (ACF), an inhibitor of HIF1?, induced the expression of adiponectin and reduced the expression of SOCS3 in cultured 3T3-L1 adipocytes. Mechanistic studies revealed that HIF1? suppressed the expression of adiponectin through a SOCS3-STAT3 pathway. Socs3 was identified as a novel HIF1? target gene based on chromatin immunoprecipitation and luciferase assays. STAT3 directly regulated adiponectin in vitro in cultured 3T3-L1 adipocytes. ACF was found to prevent diet-induced obesity and insulin resistance. In vivo, ACF also regulated the SOCS3-STAT3-adiponectin pathway, and inhibition of HIF1? in adipose tissue was essential for ACF to improve the SOCS3-STAT3-adiponectin pathway to counteract insulin resistance. This study provides evidence for a novel target gene and signal transduction pathway in adipocytes and indicates that inhibitors of HIF1? have potential utility for the treatment of obesity and type 2 diabetes.

SUBMITTER: Jiang C 

PROVIDER: S-EPMC3567639 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature