Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
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2019-12Author
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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SRC-1</jats:italic> in Pomc neurons in mice attenuates their depolarization by leptin, decreases <jats:italic>Pomc</jats:italic> expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in <jats:italic>SRC-1</jats:italic> 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-1<jats:sup>L1376P</jats:sup>), leptin-induced depolarization of Pomc neurons and <jats:italic>Pomc</jats:italic> 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.</jats:p>
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