THE METABOLIC SIGNIFICANCE OF LEPTIN IN HUMANS - GENDER-BASED DIFFERENCES IN RELATIONSHIP TO ADIPOSITY, INSULIN SENSITIVITY, AND ENERGY-EXPENDITURE

Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relations hip of leptin to metabolic abnormalities associated with obesity toget her with hormonal and substrate regulation of leptin have not been ext ensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m(2)] were characterized on a metabolic ward with regard to body composition, gl ucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had norma l glucose tolerance (50 men and 35 women), and 31 had noninsulin-depen dent diabetes mellitus (12 men and 19 women). In both men and women, f asting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat(r = 0.82 and r = 0.88, respe ctively; all P < 0.0001). However, men exhibited lower leptin levels a t any given measure of obesity. Compared with those in men, leptin lev els rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI) - 31.103 in women; leptin = 0.534 (BMI) - 8.437 in men] a nd 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat) - 24.817 in women; leptin = 0.402 (% body fat) - 3.087 in m en]. Hyperleptinemia was associated with insulin resistance (r = -0.57 ; P < 0.0001) and high waist to hip ratio (r = 0.75;P < 0.0001) only i n men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20 %) only in women. There was no correlation noted between fasting lepti n levels and either resting energy expenditure or insulin-induced ther mogenesis in men or women (P = NS). In stepwise and multiple regressio n models with leptin as the dependent variable, noninsulin-dependent d iabetes mellitus did not enter the equations at a statistically signif icant level. The data indicate that there are important gender-based d ifferences in the regulation and action of leptin in humans. Serum lep tin levels increase with progressive obesity in both men and women. Ho wever, for any given measure of obesity, leptin levels are higher in w omen than in men, consistent with a state of relative leptin resistanc e. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regula tes body fat predominantly by altering eating behavior rather than cal origenesis.