Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function.
This mouse study investigated therapeutic strategies for hyperphagia, hyperglycemia, and obesity caused by a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y), which encodes the serotonin 2C receptor (5-HT2CR). Researchers tested three main approaches in male mice fed a high-fat diet. First, they used viral re-expression of functional 5-HT2CR specifically in hypothalamic POMC neurons, finding this was sufficient to reduce food intake and body weight, and restored neuronal responsiveness to lorcaserin (a selective 5-HT2CR agonist). Second, they administered melanotan II, an MC4R agonist, which effectively suppressed feeding and weight gain. Third, they promoted voluntary wheel-running exercise, which reduced high-fat diet consumption and improved glucose homeostasis. The study highlights the importance of the 5-HT2CR–melanocortin pathway in energy balance regulation and suggests MC4R agonists and physical activity may be relevant strategies for individuals carrying rare Htr2c variants. Key limitations include exclusive use of a single male mouse model, a specific engineered mutation, and the gap between rodent models and human metabolic disease.
Why this grade: All experiments were conducted exclusively in a male mouse model carrying a specific engineered Htr2c loss-of-function mutation; no human data were included.
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.
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