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

. Ukkola O, Tremblay A, Després J‐P, Chagnon YC, Campfield LA, Bouchard C (Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; University of Oulu, Oulu, Finland; Laval University, Ste‐Foy, Québec, Canada; and University of Colorado Health Sciences Center, Denver, Colorado, USA). Leptin receptor Gln223Arg variant is associated with a cluster of metabolic abnormalities in response to long‐term overfeeding. J Intern Med 2000; 248: 435–439. Objectives. The role of the leptin receptor (LEPR) gene Gln223Arg polymorphism on the metabolic and body composition changes in response to overfeeding was studied. Subjects. Twelve pairs of male monozygotic twins ate a 4.2 MJ day –1 energy 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 curve during oral glucose tolerance tests (OGTTs) in the GlnGln ( n = 10) than in the GlnArg/ArgArg ( n = 14) subjects. In addition, the GlnGln genotype was 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 high‐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 polymorphism are more susceptible to metabolic abnormalities when they are exposed to long‐term positive energy balance. These findings provide new information on the genetic basis of individual differences in response to chronically elevated food intake.