Objective: Recent experimental work in mice has demonstrated that leptin is synthesized by muscle cells. As this latter tissue is the main target for insulin-estimulated glucose disposal, we hypothesized that the muscular and fat-free mass (FFM) compartments might influence serum leptin levels in humans through increased insulin resistance. Design and methods: We evaluated body composition (through bioelectric impedance and anthropometrical parameters), insulin resistance (using the fasting

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... ing the fasting insulin resistance index (FIRI) and insulin sensitivity (S I ) from the minimal model analysis) and leptin levels in 140 men and 114 women. Results: Serum insulin, FIRI and leptin levels were significantly increased in men in the highest quintile of FFM. Leptin levels positively correlated with FFM in men (r = 0.24, P = 0004) but not in women (r = 0.02, P = not significant). With weight gain, however, approximately 25% of the additional weight is lean mass, so that obese people have higher fat-free mass than lean people. Hence, we performed a multiple linear regression analysis in a stepwise manner to predict leptin levels, in which fat mass (FM), FFM, and FIRI, but not age or waist-to-hip ratio (WHR) independently contributed to 32%, 6% and 3% of the variance in serum leptin levels in men. In women, FM (49%), FIRI (3.6%) and WHR (2.4%), but not FFM or age explained this variance. In a sample of 40 subjects, S I and leptin correlated with midarm muscle circumference (r = ¹0.51, P = 0.03 and r = 0.53, P = 0.02) and mid-arm muscle area (r = ¹0.52, P = 0.03 and r = 0.53, P = 0.02) in men (n = 17) but not in women (n = 23). Conclusions: The fat-free mass compartment contributes to the variability of serum leptin levels in men. Whether insulin resistance at this level mediates an increased production of leptin merits further research.