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
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
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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: |
Date | Event |
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12 April 2019 | Published | 21 January 2019 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
Project ID | Funder | Funder ID |
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R01 CA193455 | NCI NIH HHS | UNSPECIFIED | P01 DK113954 | NIDDK NIH HHS | UNSPECIFIED | R01 DK101379 | NIDDK NIH HHS | UNSPECIFIED | P01 DK059820 | NIDDK NIH HHS | UNSPECIFIED | R01 HD007857 | NICHD NIH HHS | UNSPECIFIED | R01 DK114279 | NIDDK NIH HHS | UNSPECIFIED | P30 CA125123 | NCI NIH HHS | UNSPECIFIED | R01 DK117281 | NIDDK NIH HHS | UNSPECIFIED | R01 DK093587 | NIDDK NIH HHS | UNSPECIFIED | 098497/Z/12/Z | Wellcome Trust | UNSPECIFIED | R01 CA112403 | NCI NIH HHS | UNSPECIFIED | R01HD008818 | National Institutes of Health | http://dx.doi.org/10.13039/100000002 | 6250-51000-059-04S | United States Department of Agriculture | UNSPECIFIED | NSFC 81873558 | Chinese National Natural Science Foundation | UNSPECIFIED | RP170005 | Cancer Prevention and Research Institute of Texas | http://dx.doi.org/10.13039/100004917 | P30CA125123 | National Cancer Institute | http://dx.doi.org/10.13039/100000054 | WT098051 | Wellcome Trust | http://dx.doi.org/10.13039/100004440 | 203513/Z/16/Z | Wellcome Trust | http://dx.doi.org/10.13039/100004440 |
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PubMed ID: |
30979869 |
Web of Science ID: |
WOS:000464338100029 |
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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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