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

Abstract

Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/obmice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism 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 oxidation 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 antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the 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 3-kinase inhibitor wortmannin blocked insulin’s effects on lipid metabolism but only attenuated leptin’s effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulin’s promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

“…The lower end of the results [19] [20] [45] are similar to that observed in the present study with muscle incubation. The higher values (but not the highest) [46] [47] are comparable to the results of the present study obtained using the model with 13 C-palmitate tracers. Using muscle homogenate, the results were even lower [48].…”

Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane

“…In addition, we (13) and others (22) have demonstrated recently that the insulin-induced alterations in fatty acid metabolism are prevented when the activity of PI 3-kinase is inhibited by either wortmannin (22) or LY-294002 (13).…”

“…For example, in skeletal muscle, insulin can inhibit fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I, an effect that is mediated through increased intracellular levels of malonyl-CoA (4,14). It has now also been shown that insulin increases fatty acid esterification into triacylglycerols in skeletal muscle while simultaneously reducing fatty acid oxidation (13,22). From these studies, it can also be inferred that insulin increases net fatty acid uptake into the myocyte, since the insulininduced increase in fatty acid esterification was markedly greater than the insulin-induced inhibition of fatty acid oxidation.…”

“…Whether FAT/CD36 distribution within the myocyte is also regulated by insulin is not known, but because insulin increases net fatty acid uptake (13,22) via a phosphatidylinositol (PI) 3-kinase-dependent mechanism (13,22), and because it it is well known that insulin induces the translocation of the glucose transporter GLUT-4 via PI 3-kinase activation, it is reasonable to hypothesize that insulin increases fatty acid uptake by muscle by translocating FAT/CD36 from its intracellular compartments to the plasma membrane. Therefore, in the present studies, we have examined the effects of insulin on 1) fatty acid uptake and metabolism in perfused rat skeletal muscle and 2) on the translocation of FAT/CD36 from its intracellular compartment to the plasma membrane.…”

Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels

“…Systemic or central administration of leptin reduces feed intake in rodents, chickens, pigs, and sheep [1,13,15,24] and while data from livestock species remains sparse, leptin appears to be an important component of a feedback loop involving key metabolic regulators including insulin, glucocorticoids and the sympathetic nervous system [16]. Finally, in vitro studies suggest that leptin can directly modulate energy metabolism in peripheral tissues and may antagonize insulin activities in adipose [21] and muscle [22]. These physiological properties support leptin as a strong candidate gene for evaluation of genetic polymorphisms that could affect carcass fat content in cattle.…”