Gene Number: 4160

Location: 18q21.32

Key Functions: Appetite regulation, energy balance, body weight control, glucose metabolism

MC4R encodes the melanocortin 4 receptor, a G protein-coupled receptor (GPCR) that is predominantly expressed in the hypothalamus, particularly within the arcuate nucleus. This receptor plays a central role in the regulation of energy homeostasis by integrating hormonal and neuronal signals related to nutrient status, satiety, and energy expenditure. Activation of MC4R by endogenous ligands such as α-melanocyte-stimulating hormone (α-MSH) triggers intracellular signaling cascades involving cyclic AMP (cAMP) and downstream protein kinase pathways, which modulate neuronal activity controlling feeding behavior and metabolic processes.

MC4R regulates the expression and activity of pathways involved in:

1. Appetite regulation:MC4R mediates satiety signals by responding to α-MSH, a product of the proopiomelanocortin (POMC) gene, while being antagonized by agouti-related peptide (AgRP). Proper MC4R function suppresses food intake, promoting a balance between energy consumption and expenditure.

2. Energy expenditure:MC4R signaling affects sympathetic nervous system activity, which in turn regulates basal metabolic rate, thermogenesis, and overall energy expenditure. Dysregulation can lead to decreased energy utilization and increased fat accumulation.

3. Body weight control:Through its dual effects on appetite suppression and energy expenditure, MC4R plays a pivotal role in maintaining body weight homeostasis. Loss-of-function variants or mutations in MC4R are strongly associated with early-onset obesity, hyperphagia, and increased adiposity, making them among the most common monogenic contributors to human obesity.

4. Glucose metabolism:MC4R influences peripheral glucose homeostasis indirectly via regulation of body weight and energy balance. Activation of hypothalamic MC4R pathways enhances insulin sensitivity and supports glucose regulation, whereas impaired signaling can contribute to metabolic dysregulation, including insulin resistance and increased risk for type 2 diabetes.

Clinical and physiological significance:Variants in MC4R have been extensively studied in both human and animal models, demonstrating that functional disruptions lead to increased food intake, reduced energy expenditure, and a predisposition to severe obesity from childhood. Beyond monogenic obesity, polymorphisms in MC4R have been linked to variation in body mass index (BMI), feeding behavior, and susceptibility to metabolic disorders in the general population. This underscores MC4R as a critical molecular hub for energy homeostasis and a promising target for therapeutic interventions aimed at obesity and related metabolic diseases.