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.

Additional Metadata
Persistent URL dx.doi.org/10.1038/s41467-019-08737-6, hdl.handle.net/1765/116120
Journal Nature Communications
Yang, Y.J., van der Klaauw, A.A, Zhu, L.R., Cacciottolo, T.M., He, Y.L., & Stadler, L.K.J. (2019). Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nature Communications, 10. doi:10.1038/s41467-019-08737-6