Obesity and Adiponectin Gene Expression

  • Shao, Jianhua (PI)

Grants and Contracts Details


Adiponectin is an adipose-derived hormone that sensitizes insulin sensitivity with anti-atherogenic property. Hypoadiponectinemia has been considered as an independent risk factor for cardiovascular diseases. Adiponectin gene expression is reversely correlated with adipocity. However, the molecular mechanisms that regulate adiponectin expression and the causative mechanisms that impair adiponectin gene expression in obesity 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. Moreover, SIRT1 regulates Fox01 function through reversible de-acetylation. Our preliminary studies demonstrate that Fox01 up-regulates adiponectin gene transcription through a Fox01 responding region in the adiponectin promoter that contains three adjacent putative Fox01 binding sites. Fox01-mediated adiponectin transcription regulation is not solely dependent on Fox01 transactivation activity, but also involves other transcription factors including C/EBPalpha. Our studies revealed that Foxo1 interacts with C/EBPalpha and recruits C/EBPalpha to the adiponectin promoter. Most importantly, SIRT1 synergistically enhances Fox01 and C/EBPalpha-mediated 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/EBPalpha 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 Specific Aim 1, we will further define the molecular mechanisms by which SIRT1 and Fox01/C/EBPalpha transcription complex regulate adiponectin gene transcription. In Specific Aim 2, we will extend our in-vitro findings into high-fat diet induced obese mouse model. The role of SIRT1 in controlling adiponectin gene expression will also be further studied by using adipose-specific SIRT1 transgenic mice. The studies will provide novel insights into the modulation of transcription complex formation in controlling adiponectin expression. Ultimately, these studies will not only enrich our knowledge of the transcriptional regulation of adiponectin expression but also eventually lead to the discovery of pathogenic mechanisms for the diminished adiponectin expression in obesity.
Effective start/end date7/1/066/30/08


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