Journal Article

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

Zhu, Liangru, Yan, Xiaofeng, van der Klaauw, Agatha A., Stadler, Lukas K. J., Yang, Yongjie, Saito, Kenji, Henning, Elana, He, Yanlin, Wang, Chunmei, Liao, Lan, Hinton, Antentor, Farooqi, I. Sadaf, Xu, Jianming, Xu, Yong, O’Rahilly, Stephen, Keogh, Julia M., Lawler, Katherine L., Xu, Pingwen, Hendricks, Audrey E., Mistry, Vanisha, Tong, Qingchun, Bochukova, Elena G., Inês Barroso, Banton, Matthew C., Cacciottolo, Tessa M., O’Malley, Bert W.

2019

Overview

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-1 L1376P ), 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. Neurons expressing pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here the authors show that Steroid Receptor Coactivator-1 (SRC-1) regulates the function of Pomc expressing neurons, and that rare heterozygous variants found in obese individuals lead to loss of SRC-1 function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/15 / 631/378/1488/393 / 64/60 / 692/163/2743/393 / 96/95 / Alleles / Animals / Body Weight / Body weight loss / Cell Line, Tumor / Clonal deletion / Crosses, Genetic / Depolarization / Energy balance / Food / Food intake / Gene Deletion / Gene Knock-In Techniques / Genetic Variation / HEK293 Cells / Heterozygote / High fat diet / Homeostasis / Humanities and Social Sciences / Humans / Hypothalamus / Hypothalamus - metabolism / Leptin - metabolism / Male / Membrane Potentials / Mice / Mice, Transgenic / multidisciplinary / Mutation, Missense / Neurons / Neurons - metabolism / Nuclear Receptor Coactivator 1 - genetics / Nuclear Receptor Coactivator 1 - metabolism / Obesity / Obesity - genetics / Obesity - metabolism / Phenotype / Proopiomelanocortin / Receptor mechanisms / Rodents / Science / Science (multidisciplinary) / Stat3 protein / Steroid receptor coactivator 1 / Steroids / Transcription / Weight loss