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

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

doi:10.1038/s41467-019-08737-6

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.

Highlights

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight
To directly test whether rare human Steroid Receptor Coactivator-1 (SRC-1) variants contribute to Pomc neuron function and/or energy homeostasis, we generated a knock-in mouse model of a human variant which results in a severe loss of function in cells, Steroid receptor coactivator (SRC)-1L1376P (Fig. 4a)
We demonstrated that in the hypothalamus, the coactivator SRC-1 modulates the ability of leptin to regulate the expression of the anorectic peptide POMC by directly interacting with phosphorylated STAT3, a known product of leptin-receptor activation

Summary

Introduction

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. 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 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. An increase in leptin levels leads to the activation of neurons expressing the anorectic peptide Pro-opiomelanocortin (POMC) leading to a reduction in food intake[8]. We generated a knock-in mouse model of the most severe loss of function human SRC-1 variant and characterized the metabolic consequences of these mutant mice

Methods

Results

Conclusion