Transcriptional Regulation of Adiponectin Gene Expression

Adiponectin is an adipose-derived hormone that plays a critical role in maintaining energy and glucose metabolism. Diminished adiponectin gene expression and low blood concentration have been well documented in both obesity and type 2 diabetes. However, the molecular mechanisms that regulate adiponectin expression and the causative mechanisms that impair adiponectin gene expression in obesity and type 2 diabetes remain poorly understood. Recent studies have indicated that forkhead transcription factor 01 (Foxo1) and silent information regulator 2 (SIR2) mammalian ortholog SIRT1 are involved in adipogenesis. Both are induced by calorie restriction and contribute to longevity. Moreover, SIRT1 regulates Fox01 function through reversible de-acetylation. Our preliminary studies demonstrate that Fox01 upregulates adiponectin gene transcription through a Fox01 responding region in the adiponectin promoter that contains three adjacent putative Fox01 binding sites. Further, Fox01-mediated adiponectin transcription regulation is not solely dependent on Fox01 transactivation activity, but also involves other transcription factors including C/EBPa. Our studies revealed that Fox01 interacts with C/EBPa and enhances C/EBPa binding to the adiponectin promoter. Most importantly, SIRT1 synergistically enhances Fox01 and C/EBPamediated adiponectin promoter activation. In addition, low SIRT1 and Fox01 expression were detected in adipose tissues of high fat diet-induced obese mice and db/db diabetic mice. These data suggest that Fox01 and C/EBPa interact to promote formation of a transcription complex at the adiponectin promoter and that SIRT1 enhances the formation of this complex which up-regulates adiponectin gene transcription. In this proposal we will further define the molecular mechanisms by which Fox01 and SIRT1 regulate adiponectin gene transcription. The studies will provide novel insights into the modulation of transcription complex formation in controlling adiponectin expression. Using high fat diet-induced obese mice and pair-feeding approaches, the involvement and role of adiposity and high fat diet in impairing Fox01 and SIRT1 expression and function will be studied. Ultimately, these studies will not only enrich our knowledge of the transcriptional regulation of adiponectin expression but also eventually lead to the discovery of pathoqenic mechanisms for the diminished adiponectin expression in obesity and diabetes.