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Nat Commun. 2019 Apr 12;10(1):1718. doi: 10.1038/s41467-019-08737-6.

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

Author information

1
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
2
University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
3
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, 430022, China.
4
Wellcome Sanger Institute, Cambridge, CB10 1SA, UK.
5
Mathematical and Statistical Sciences Department, University of Colorado - Denver, Denver, CO, 80204, USA.
6
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
7
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
8
University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. isf20@cam.ac.uk.
9
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. yongx@bcm.edu.
10
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. yongx@bcm.edu.

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.

PMID:
30979869
PMCID:
PMC6461669
DOI:
10.1038/s41467-019-08737-6
[Indexed for MEDLINE]
Free PMC Article

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