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

Yang, Y; van der Klaauw, AA; Zhu, L; Cacciottolo, TM; He, Y; Stadler, LKJ; Wang, C; Xu, P; Saito, K; Hinton, A; et al. Yang, Y; van der Klaauw, AA; Zhu, L; Cacciottolo, TM; He, Y; Stadler, LKJ; Wang, C; Xu, P; Saito, K; Hinton, A; Yan, X; Keogh, JM; Henning, E; Banton, MC; Hendricks, AE; Bochukova, EG; Mistry, V; Lawler, KL; Liao, L; Xu, J; O'Rahilly, S; Tong, Q; UK10K Consortium; Inês Barroso; O'Malley, BW; Farooqi, IS; Xu, Y (2019) Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nat Commun, 10 (1). p. 1718. ISSN 2041-1723 https://doi.org/10.1038/s41467-019-08737-6
SGUL Authors: Jamshidi, Yalda Whincup, Peter Hynes

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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.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
Keywords: UK10K Consortium, MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
12 April 2019Published
21 January 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
R01 CA193455NCI NIH HHSUNSPECIFIED
P01 DK113954NIDDK NIH HHSUNSPECIFIED
R01 DK101379NIDDK NIH HHSUNSPECIFIED
P01 DK059820NIDDK NIH HHSUNSPECIFIED
R01 HD007857NICHD NIH HHSUNSPECIFIED
R01 DK114279NIDDK NIH HHSUNSPECIFIED
P30 CA125123NCI NIH HHSUNSPECIFIED
R01 DK117281NIDDK NIH HHSUNSPECIFIED
R01 DK093587NIDDK NIH HHSUNSPECIFIED
098497/Z/12/ZWellcome TrustUNSPECIFIED
R01 CA112403NCI NIH HHSUNSPECIFIED
R01HD008818National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
6250-51000-059-04SUnited States Department of AgricultureUNSPECIFIED
NSFC 81873558Chinese National Natural Science FoundationUNSPECIFIED
RP170005Cancer Prevention and Research Institute of Texashttp://dx.doi.org/10.13039/100004917
P30CA125123National Cancer Institutehttp://dx.doi.org/10.13039/100000054
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
203513/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 30979869
Web of Science ID: WOS:000464338100029
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110831
Publisher's version: https://doi.org/10.1038/s41467-019-08737-6

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