Children’s Nutrition Research Center Staff Publications
Publication Date
4-12-2019
Journal
Nature Communications
DOI
10.1038/s41467-019-08737-6
PMID
30979869
PMCID
PMC6461669
PubMedCentral® Posted Date
4-12-2019
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Alleles, Animals, Body Weight, Cell Line, Tumor, Crosses, Genetic, Gene Deletion, Gene Knock-In Techniques, Genetic Variation, HEK293 Cells, Heterozygote, Homeostasis, Humans, Hypothalamus, Leptin, Male, Membrane Potentials, Mice, Mice, Transgenic, Mutation, Missense, Neurons, Nuclear Receptor Coactivator 1, Obesity, Phenotype
Abstract
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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons