Plasma leptin levels: interaction of obesity with a common variant of insulin receptor substrate-1.

Obesity is associated with insulin resistance and other major cardiovascular risk factors. A common amino acid polymorphism at codon 972 of the insulin receptor substrate-1 (IRS-1) has been shown to interact with obesity in the expression of insulin resistance. The plasma concentration of the adipocyte-specific hormone leptin is increased in obesity and is correlated with adipose tissue mass. Because in vitro studies demonstrated inhibitory effects of leptin on insulin signaling, leptin may be involved in obesity-associated insulin resistance. To gain insight into the relationship between insulin and leptin in obesity, we studied plasma leptin levels and several cardiovascular risk factors, as well as their modification by the IRS-1 codon 972 genotype, in 156 obese individuals and 131 lean control subjects. In both groups, 10% of the subjects were heterozygous for the IRS-1 codon 972 variant. Obese individuals harboring the IRS-1 variant displayed significantly lower plasma concentrations of leptin than obese subjects without the polymorphism (means, 26.7 versus 37.8 ng/mL, P<0.0293). In a subgroup of obese patients, leptin mRNA abundance was measured in the adipose tissue and was significantly lower in carriers of the IRS-1 variant than in subjects with the wild-type variant (P<0.0291). Our data suggest that insulin signaling influences plasma leptin concentrations at the mRNA expression level and argue against leptin as a major causative factor of insulin resistance.