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Nat Commun ; 10(1): 1718, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979869

RESUMO

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.


Assuntos
Hipotálamo/metabolismo , Neurônios/metabolismo , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Obesidade/genética , Alelos , Animais , Peso Corporal , Linhagem Celular Tumoral , Cruzamentos Genéticos , Deleção de Genes , Técnicas de Introdução de Genes , Variação Genética , Células HEK293 , Heterozigoto , Homeostase , Humanos , Leptina/metabolismo , Masculino , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Obesidade/metabolismo , Fenótipo
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