PLASMA LEPTIN LEVELS - INTERACTION OF OBESITY WITH A COMMON VARIANT OF INSULIN-RECEPTOR SUBSTRATE-1

Obesity is associated with insulin resistance and other major cardiova scular risk factors. A common amino acid polymorphism at codon 972 of the insulin receptor substrate-1 (IRS-1) has been shown to interact wi th obesity in the expression of insulin resistance. The plasma concent ration of the adipocyte-specific hormone leptin is increased in obesit y and is correlated with adipose tissue mass. Because in vitro studies demonstrated inhibitory effects of leptin on insulin signaling, lepti n may be involved in obesity-associated insulin resistance. To gain in sight 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% o f the subjects were heterozygous for the IRS-1 codon 972 variant. Obes e individuals harboring the IRS-1 variant displayed significantly lowe r plasma concentrations of leptin than obese subjects without the poly morphism (means, 26.7 versus 37.8 ng/mL, P<0.0293). In a subgroup of o bese patients, leptin mRNA abundance was measured in the adipose tissu e and was significantly lower in carriers of the IRS-I 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.