Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
12 April 2019
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| In: |
Nature Communications
Year: 2019, Volume: 10 |
| ISSN: | 2041-1723 |
| Online Access: |
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| Author Notes: | Yongjie Yang, Agatha A. van der Klaauw, Liangru Zhu, Tessa M. Cacciottolo, Yanlin He, Lukas K.J. Stadler, Chunmei Wang, Pingwen Xu, Kenji Saito, Antentor Hinton, Xiaofeng Yan, Julia M. Keogh, Elana Henning, Matthew C. Banton, Audrey E. Hendricks, Elena G. Bochukova, Vanisha Mistry, Katherine L. Lawler, Lan Liao, Jianming Xu, Stephen O'Rahilly, Qingchun Tong, UK10K Consortium, Inês Barroso, Bert W. O'Malley, I. Sadaf Farooqi & Yong Xu |
| Summary: | 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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| Item Description: | Gesehen am 29.05.2019 UK10K Consortium: Yongjie Yang, Winfried März [und weitere] |
| Physical Description: | Online Resource |
| ISSN: | 2041-1723 |