Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods

Area of Science:

• Neuroscience
• Endocrinology
• Genetics

Background:

• Haploinsufficiency of the melanocortin-4 receptor (MC4R) is the most common genetic cause of severe early-onset obesity.
• MC4R signaling is implicated in feeding behavior and macronutrient intake, with inhibition potentially increasing high-fat food consumption.

Purpose of the Study:

• To investigate the chronic feeding preferences in mice with partial or complete MC4R deletion, modeling human melanocortin obesity syndrome.
• To determine if MC4R deficiency alters preference for palatable high-fat or high-carbohydrate foods.

Main Methods:

• Utilized two-choice diet paradigms comparing high-fat, high-carbohydrate, and normal chow in wild-type and MC4R-deficient mice (heterozygous and homozygous).
• Assessed feeding behavior and food preference over chronic exposure to different dietary options.

Main Results:

• Deletion of one MC4R allele had no effect on feeding preference.
• Deletion of both MC4R alleles paradoxically decreased preference for palatable high-fat and high-sucrose foods.
• Both heterozygous and homozygous MC4R-deficient mice exhibited hyperphagia, consuming more standard chow when presented with dietary variety.

Conclusions:

• Decreased MC4R signaling consistently leads to hyperphagia in melanocortin obesity syndrome, regardless of food type.
• Hyperphagia in this model appears driven by dietary variety or novelty, rather than an increased preference for high-fat or high-carbohydrate foods.