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

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UK10K Consortium , Yang , Y , van der Klaauw , A A , Lonnqvist , J , Palotie , A , Paunio , T , Pietilainen , O & Suvisaari , J 2019 , ' Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis ' , Nature Communications , vol. 10 , 1718 . https://doi.org/10.1038/s41467-019-08737-6

Title: Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
Author: UK10K Consortium; Yang, Yongjie; van der Klaauw, Agatha A.; Lonnqvist, Jouko; Palotie, Aarno; Paunio, Tiina; Pietilainen, Olli; Suvisaari, Jaana
Contributor: University of Helsinki, HUS Psychiatry
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Department of Psychiatry
University of Helsinki, Center for Population, Health and Society
University of Helsinki, National Institute for Health and Welfare (THL)
Date: 2019-04-12
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/301508
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.
Subject: LEPTIN RESISTANCE
PROOPIOMELANOCORTIN NEURONS
SIGNAL TRANSDUCER
SOCS-3 EXPRESSION
FOOD-INTAKE
PPAR-GAMMA
ER STRESS
OBESITY
BALANCE
FOXO1
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
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