Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice

Because muscle triacylglycerol (TAG) accumulation might contribute to insul in resistance in leptin-deficient ob/ob mice, we studied the acute (60- to 90-min) effects of leptin and insulin on [C-14]glucose and [C-14]oleate met abolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus , leptin decreased glycogen synthesis 36-46% (P < 0.05), increased oleate o xidation 26% (P < 0.05), decreased oleate incorporation into TAG 32% (P < 0 .05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% (P < 0.05). Insulin decreased oleate oxidation 31% (P < 0.05), increased oleate incorporation into TAG 46% (P < 0.05), and increased the partitioning ratio 125% (P < 0.01). Adding leptin diminished insulin's anti oxidative, lipogenic effects. In soleus from lean mice, insulin increased t he partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M., G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol S-kinas e inhibitor wortmannin blocked insulin's effects on lipid metabolism but on ly attenuated leptin's effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogen esis is independent of increased glucose uptake. These data indicate that l eptin opposes insulin's promotion of TAG accumulation in lean and ob/ob mus cles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to requir e other long-term factors, possibly TAG depletion.