期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-08737-6
关键词
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资金
- NIH [R01DK093587, R01DK101379, R01DK117281, R01DK114279, R01CA112403, R01CA193455, R01HD07857, R01HD008818, P01DK059820, P0101DK113954]
- USDA/CRIS [6250-51000-059-04S]
- American Heart Association
- Chinese National Natural Science Foundation [NSFC 81873558]
- Cancer Prevention and Research Institute of Texas [RP170005]
- NCI Cancer Center Support Grant [P30CA125123]
- USDA ARS
- Wellcome Trust [098497/Z/12/Z, WT098051, 203513/Z/16/Z]
- NIHR Cambridge Biomedical Research Centre
- Bernard Wolfe Health Neuroscience Endowment
- Philip Greenwood Clinical Research Fellowship
- Wellcome Trust Research Training Fellowship
- MRC [MC_UU_00014/1, MC_UU_12012/1] Funding Source: UKRI
- Wellcome Trust [098497/Z/12/Z, 203513/Z/16/Z] Funding Source: Wellcome Trust
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.
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