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Hypothalamic Leptin Signaling Regulates Hepatic Insulin Sensitivity via a Neurocircuit Involving the Vagus Nerve

Diabetes and Obesity Center of Excellence (J.G., F.K., M.W.S., G.J.M.), Department of Medicine, University of Washington, Seattle, Washington 98195; Departments of Medicine and Neuroscience (G.J.S.), Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461; Department of Molecular Biosciences (P.J.H.), School of Veterinary Medicine, and Department of Nutrition, University of California, Davis, Davis, California 95616; and Kovler Diabetes Center (C.J.R.), Department of Medicine, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Gregory J. Morton, Department of Medicine, University of Washington at South Lake Union, 815 Mercer Street, Box 358055, Seattle, Washington 98195. E-mail: gjmorton{at}u.washington.edu.

Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fa^k/fa^k) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.