Children’s Nutrition Research Center Staff Publications
Language
English
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
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.
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
Published Open-Access
yes
Recommended Citation
Yang, Yongjie; van der Klaauw, Agatha A; Zhu, Liangru; et al., "Steroid Receptor Coactivator-1 Modulates the Function of Pomc Neurons and Energy Homeostasis" (2019). Children’s Nutrition Research Center Staff Publications. 157.
https://digitalcommons.library.tmc.edu/staff_pub/157
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons