Leptin receptor Gln223Arg variant is associated with a cluster of metabolic abnormalities in response to long-term overfeeding

Objectives. The role of the leptin receptor (LEPR) gene Gln223Arg polymorph ism on the metabolic and body composition changes in response to overfeedin g was studied. Subjects. Twelve pairs of male monozygotic twins ate a 4.2 MJ day(-1) energ y surplus, 6 days week(-1) during a period of 100 days. Results. Overfeeding induced a significantly greater increase in glucose (P = 0.001 for percentage change) and insulin (P = 0.038) areas under the cur ve during oral glucose tolerance tests (OGTTs) in the GlnGln (n = 10) than in the GlnArg/ArgArg (n = 14) subjects, In addition, the GlnGln genotype Mr as associated with a greater increase in plasma levels of leptin (P = 0.037 ) and total triglycerides (P = 0.003), as well as a greater decrease in hig h-density lipoprotein cholesterol (P = 0.010), than for the combined GlnArg /ArgArg genotypes. Body composition changes were not different between the genotypes. Conclusions. We conclude that the GlnGln subjects of the LEPR gene polymorp hism are more susceptible to metabolic abnormalities when they are exposed to long-term positive energy balance. These findings provide new informatio n on the genetic basis of individual differences in response to chronically elevated food intake.