Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis.
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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 impair 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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2041-1723
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Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (099038/Z/12/Z)
Addenbrooke's Charitable Trust (ACT) (9273 Minute No 24/15 A)
Wellcome Trust (203513/Z/16/Z)
Wellcome Trust (098497/Z/12/Z)
Medical Research Council (MC_UU_12012/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
MRC (MC_UU_00014/1)
Medical Research Council (MC_PC_12012)