Obesity is associated with
insulin resistance, particularly when body fat has a central distribution. However,
insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean
insulin-resistant individuals have greater amounts of body fat than lean
insulin-sensitive subjects. Alternatively, their body fat distribution may be different.
Obesity is associated with elevated plasma
leptin levels, but some studies have suggested that
insulin sensitivity is an additional determinant of circulating
leptin concentrations. To examine how body fat distribution contributes to
insulin sensitivity and how these variables are related to
leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean
insulin-sensitive (LIS, n = 56), lean
insulin-resistant (LIR, n = 61), and obese
insulin-resistant (OIR, n = 57) based on their BMI and
insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma
leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity,
insulin sensitivity, and
leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting
insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting
leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar
leptin levels, whereas their intra-abdominal fat and
insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with
insulin resistance, whereas subcutaneous fat deposition correlates with circulating
leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between
insulin resistance and elevated circulating
leptin concentrations in lean and obese subjects.