Are LEPR rs1137101 and MC4R rs17782313 variants linked to higher appetite and obesity risk?

Hypothalamic energy homeostasis is highly regulated by leptin and melanocortin signaling. Polymorphisms within the genes governing these pathways serve as key genetic determinants of appetite, adiposity, and overall obesity risk.

Clinical evidence

• LEPR rs1137101: A meta-analysis of 39 studies demonstrates that the GG genotype is significantly associated with obesity susceptibility (OR ≈ 1.39) across Asian and Caucasian cohorts, correlating with increased body weight and waist circumference.
• MC4R rs17782313: Homozygous CC carriers exhibit an increased risk of obesity (OR ≈ 1.38). This variant is tied to higher daily energy intake and a ~25% reduction in postprandial satiation, predisposing individuals to frequent snacking and higher subjective hunger.

Mechanistic explanations

• Leptin receptor impairment: The LEPR rs1137101 (Q223R) missense mutation alters the receptor's extracellular domain, which impairs leptin binding and leads to functional leptin resistance. This directly blunts essential hypothalamic satiety feedback.
• Disrupted melanocortin signaling: Downstream in the signaling cascade, the MC4R rs17782313 variant impairs melanocortin receptor pathway signaling. This disruption reduces postprandial satiation and biases individuals toward persistent hunger and elevated adiposity.

Bottom line

• Bottom line: Genetic variants in LEPR (rs1137101) and MC4R (rs17782313) are significantly associated with susceptibility to higher appetite, adiposity, and obesity. They undermine central neuroendocrine satiety systems, providing a biological basis for elevated hunger and polygenic obesity risk.