Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis.
Yongjie YangAgatha A van der KlaauwLiangru ZhuTessa M CacciottoloYanlin HeLukas K J StadlerChunmei WangPingwen XuKenji SaitoAntentor HintonXiaofeng YanJulia M KeoghElana HenningMatthew C BantonAudrey E HendricksElena G BochukovaVanisha MistryKatherine L LawlerLan LiaoJianming XuStephen I O'RahillyQingchun Tongnull nullInês A BarrosoBert W O' MalleyDavid R FitzPatrickYong XuPublished in: Nature communications (2019)
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.
Keyphrases
- body weight
- weight loss
- high fat diet induced
- tyrosine kinase
- spinal cord
- insulin resistance
- metabolic syndrome
- mouse model
- poor prognosis
- type diabetes
- binding protein
- adipose tissue
- endothelial cells
- copy number
- cell proliferation
- roux en y gastric bypass
- spinal cord injury
- gene expression
- early onset
- gastric bypass
- drug induced