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

Yongjie Yang, Agatha A. Klaauw, Liangru Zhu, Tessa M. Cacciottolo, Yanlin He, Lukas K. J. Stadler, Chunmei Wang, Pingwen Xu, Kenji Saito, Antentor Hinton, Xiaofeng Yan, Julia M. Keogh, Elana Henning, Matthew C. Banton, Audrey E. Hendricks, Elena G. Bochukova, Vanisha Mistry, Katherine L. Lawler, Lan Liao, Jianming Xu, Stephen O’Rahilly, Qingchun Tong, Inês Barroso, Bert W. O’Malley, I. Sadaf Farooqi () and Yong Xu ()
Additional contact information
Yongjie Yang: One Baylor Plaza
Agatha A. Klaauw: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Liangru Zhu: One Baylor Plaza
Tessa M. Cacciottolo: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Yanlin He: One Baylor Plaza
Lukas K. J. Stadler: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Chunmei Wang: One Baylor Plaza
Pingwen Xu: One Baylor Plaza
Kenji Saito: One Baylor Plaza
Antentor Hinton: One Baylor Plaza
Xiaofeng Yan: One Baylor Plaza
Julia M. Keogh: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Elana Henning: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Matthew C. Banton: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Audrey E. Hendricks: Wellcome Sanger Institute
Elena G. Bochukova: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Vanisha Mistry: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Katherine L. Lawler: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Lan Liao: Baylor College of Medicine
Jianming Xu: Baylor College of Medicine
Stephen O’Rahilly: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Qingchun Tong: University of Texas Health Science Center at Houston
Inês Barroso: Wellcome Sanger Institute
Bert W. O’Malley: Baylor College of Medicine
I. Sadaf Farooqi: University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Yong Xu: One Baylor Plaza

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08737-6

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