The nuclear receptor coactivator, steroid receptor coactivator-2 (SRC-2) is an essential for body weight control. However, the molecular mechanisms by which SRC-2 regulates energy homeostasis are not fully understood. Here we showed that SRC-2 is highly expressed by hypothalamic pro-opiomelanocortin (POMC) neurons. We then generated mice lacking SRC-2 selectively in POMC neurons. These mutant mice were more resistance to high fat-diet-induced obesity compared to wild type littermates. In addition, we observed that the mutant mice failed to properly suppress energy expenditure during food deprivation, refeeding response after fasting was impaired in these mutant mice, which was accompanied with increased POMC gene expression in the hypothalamus, increased firing rate, and decreased mIPSE amplitude of POMC neurons. Further anxiety-like behavior tests showed the mutant mice exhibited decreased motivational state and incentive salience of the food reward, and enhanced Dopamine signaling to POMC neurons. Interestingly, SRC-2 interacts with FoxO1 in mouse hypothalamus, and this interaction was enhanced by fasting. Finally, using luciferase assay, we showed that over-expression of SRC-2 significantly suppressed POMC expression. Collectively, our results indicate that SRC-2 in POMC neurons, as a nuclear receptor coactivator, interacts with FoxO1 to amplify its transcription suppressing effects on the POMC gene, and therefore mediates the energy reserving effects of FoxO1 during food deprivation.


Y. Yang: None. Y. Xu: None.

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