Hartig SM, Bader DA, Abadie KV, Motamed M, Hamilton MP, Long W, York B, Mueller M, Wagner M, Trauner M, Chan L, Bajaj M, Moore DD, Mancini MA, McGuire SE

Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs ...

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in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified Ubc9 as a negative regulator of energy storage in human subcutaneous adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human subcutaneous adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and PPARγ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human subcutaneous adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased UCP1 expression by disrupting PPARγ binding at a critical UCP1 enhancer region. Last, Ubc9 is significantly elevated in subcutaneous adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of subcutaneous adipocyte energy homeostasis.

Date: Jul. 20, 2015

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