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

• DOI: 10.1038/s41467-019-08737-6
• Publication Date: 2019-04-12T10:02:59Z
• Authors: Yongjie Yang; Agatha A. van der...; 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; Yong Xu
• Keywords: 0301 basic medicine; Leptin; Male; FOOD-INTAKE; 590; Ppar-Gamma; Membrane Potentials; Socs-3 Expression; Mice; Nuclear Receptor Coactivator 1; Foxo1; LEPTIN RESISTANCE; Homeostasis; Gene Knock-In Techniques; Neurons; 2. Zero hunger; 0303 health sciences; FOXO1; Q; ER STRESS; Multidisciplinary Sciences; Phenotype; Er Stress; OBESITY; BALANCE; Leptin Resistance; Science & Technology - Other Topics; SIGNAL TRANSDUCER; PPAR-GAMMA; PROOPIOMELANOCORTIN NEURONS; Balance; Heterozygote; EMC NIHES-01-64-02; Science; Hypothalamus; Mutation, Missense; Mice, Transgenic; Article; 03 medical and health sciences; Food-Intake; Cell Line, Tumor; Animals; Humans; Signal Transducer; Obesity; Proopiomelanocortin Neurons; Alleles; Crosses, Genetic; SOCS-3 EXPRESSION; Science & Technology; Body Weight; Genetic Variation; HEK293 Cells; Gene Deletion

AbstractHypothalamic 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.