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.
Subject(s)
Diet, High-Fat , Hyperphagia , Obesity , Pro-Opiomelanocortin , Receptor, Melanocortin, Type 4 , Receptor, Serotonin, 5-HT2C , Animals , Receptor, Serotonin, 5-HT2C/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Male , Mice , Hyperphagia/metabolism , Hyperphagia/genetics , Pro-Opiomelanocortin/metabolism , Pro-Opiomelanocortin/genetics , Obesity/metabolism , Obesity/genetics , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Receptor, Melanocortin, Type 4/agonists , alpha-MSH/pharmacology , alpha-MSH/analogs & derivatives , Loss of Function Mutation , Hypothalamus/metabolism , Body Weight/drug effects , Eating/drug effects , Eating/physiology , Eating/genetics , Neurons/metabolism , Neurons/drug effects , Disease Models, Animal , Hyperglycemia/metabolism , Hyperglycemia/genetics , Mice, Inbred C57BL , Benzazepines , Peptides, CyclicABSTRACT
Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.
