2019-Nat Comm_SRC-1 POMC.pdf (1.32 MB)

2019-Nat Comm_SRC-1 POMC.pdf

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journal contribution
posted on 19.04.2019 by Yongjie Yang, Agatha Klaauw, liangru zhu, tessa cacciottolo, yanlin he, Lukas stadler, Chunmei Wang, pingwen Xu, Kenji saito, antentor Hinton, xiaofeng yan, lan liao, jianming xu, qingchun tong, Bert O'Malley, Sadaf Farooqi, Yong Xu

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impairs leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.

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