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Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis.

  • Yang, Yongjie
  • van der Klaauw, Agatha
  • Zhu, Liangru
  • Cacciottolo, Tessa
  • He, Yanlin
  • Stadler, Lukas KJ
  • Wang, Chunmei
  • Xu, Pingwen
  • Saito, Kenji
  • Hinton, Antentor
  • Yan, Xiaofeng
  • Keogh, Julia M
  • Henning, Elana
  • Banton, Matthew C
  • Hendricks, Audrey E
  • Bochukova, Elena G
  • Mistry, Vanisha
  • Lawler, Katherine L
  • Liao, Lan
  • Xu, Jianming
  • And 7 more
Publication Date
Feb 02, 2019
Apollo - University of Cambridge Repository
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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 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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