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Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats

Department of Medicine (W.H., A.M., N.D., M.S.-R., R.M.O.), Division of Endocrinology/Metabolism, and Department of Microbiology and Molecular Genetics (R.M.O.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Geriatric Research, Education, and Clinical Center (H.K.O.), Veterans Affairs Medical Center, and Division of Gerontology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Robert M. O'Doherty, Ph.D., University of Pittsburgh Medical Center, E1112 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261. E-mail: rmo1{at}pitt.edu.

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg · min^–1) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 µg/kg · min^–1) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (50%, P < 0.01), increased liver TGs (20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (50%, P < 0.01) and increased fatty acid oxidation (50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.