DOI: 10.2337/db23-234-lb ISSN: 0012-1797

234-LB: Cell-State Dependent Regulation of PPARg Signaling by Zbtb9 in Adipocytes

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

The discovery of new genes involved in adipocyte development and function can shed light on the pathophysiology of obesity and T2D and provide new therapeutic targets for these disorders. Towards this end, GWAS and rare variant association studies in the T2D Knowledge Portal revealed associations between ZBTB9 and T2D, BMI, and hip circumference. However, the function of ZBTB9 in organismal physiology was not known. We found that Zbtb9 plays a key role in adipocyte biology and differentiation via cell-state dependent regulation of PPARγ signaling. Zbtb9 directly interacts with the PPARγ/RXRα complex as shown by co-IP, and acts as a positive regulator of PPARγ transcriptional activity as shown by a PPARγ reporter assay, together establishing Zbtb9 as a new PPARγ cofactor. In line with these findings, endogenous PPARγ target gene expression was decreased in the context of Zbtb9 deficiency in adipocytes. Given the central role of PPARγ in adipogenesis, we also sought to investigate the role of Zbtb9 in this process. Surprisingly, loss of Zbtb9 in preadipocytes increased adipogenesis and the expression of adipogenic genes, including PPARγ. Transcriptome analysis prior to and during adipogenesis revealed enhanced expression of E2F target genes prior to the initiation of differentiation and later induction of adipogenic gene expression. Treatment of Zbtb9 deficient preadipocytes with an E2F1 inhibitor (HLM006474) blocked the effects of Zbtb9 deficiency on adipogenic gene expression and adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of PPARγ expression via altered E2F1 signaling. We further demonstrated that E2F1 activation by Zbtb9 is associated with increased phosphorylation of Rb, which is known to cause dissociation of the Rb/E2F complex, and activation of E2F. Our findings revealed cell-state dependent roles of Zbtb9 in adipocytes, identifying a new molecule that may be important in the pathogenesis and treatment of obesity and T2D.


X. Xu: None. D. Buchner: None.


National Institutes of Health (DK119305)

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