Language
English
Publication Date
5-27-2024
Journal
Endocrinology
DOI
10.1210/endocr/bqae063
PMID
38815086
PMCID
PMC12785533
PubMedCentral® Posted Date
1-10-2026
PubMedCentral® Full Text Version
PMC12785533
Abstract
The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.
Keywords
Animals, Receptor, Serotonin, 5-HT2C, Male, Mice, Hyperphagia, Pro-Opiomelanocortin, Diet, High-Fat, Obesity, Receptor, Melanocortin, Type 4, alpha-MSH, Loss of Function Mutation, Hypothalamus, Body Weight, Eating, Neurons, Disease Models, Animal, Hyperglycemia, Mice, Inbred C57BL, Benzazepines, Peptides, Cyclic
Published Open-Access
yes
Recommended Citation
Liu, Hailan; Liu, Zhaoxun; Wong, HueyXian Kelly; et al., "Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function" (2024). Faculty, Staff and Students Publications. 6284.
https://digitalcommons.library.tmc.edu/baylor_docs/6284