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The Journal of Neuroscience, November 21, 2007, 27(47):12924-12932; doi:10.1523/JNEUROSCI.2443-07.2007

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Behavioral/Systems/Cognitive
Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

Neel S. Singhal,^1,3 Mitchell A. Lazar,^1,2 and Rexford S. Ahima^1,2,3

¹Division of Endocrinology, Diabetes, and Metabolism, ²Institute for Diabetes, Obesity and Metabolism, and ³Neuroscience Graduate Group, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Rexford S. Ahima, University of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 715 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104. Email: ahima{at}mail.med.upenn.edu

Sensing of peripheral hormones and nutrients by the hypothalamus plays an important role in maintaining peripheral glucose homeostasis. The hormone resistin impairs the response to insulin in liver and other peripheral tissues. Here we demonstrate that in normal mice resistin delivered in the lateral cerebral ventricle increased endogenous glucose production during hyperinsulinemic-euglycemic clamp, consistent with induction of hepatic insulin resistance. In agreement, central resistin inhibited Akt phosphorylation and increased the expression of glucose-6-phosphatase, the enzyme regulating glucose output in the liver. Central resistin induced expression of proinflammatory cytokines as well as suppressor of cytokine signaling-3, a negative regulator of insulin action in liver. Central infusion of resistin was associated with neuronal activation in the arcuate, paraventricular and dorsomedial nuclei, and increased neuropeptide Y (NPY) expression in the hypothalamus. The effects of central resistin on glucose production as well as hepatic expression of proinflammatory cytokines were abrogated in mice lacking NPY. Pretreatment of wild-type mice with antagonists of the NPY Y1 receptor, but not the Y5 receptor, also prevented the effects of central resistin. Together, these results suggest that resistin action on NPY neurons is an important regulator of hepatic insulin sensitivity.

Key words: resistin; hypothalamus; NPY; liver; insulin; glucose; clamp

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Received May 29, 2007; revised Oct. 12, 2007; accepted Oct. 12, 2007.

Correspondence should be addressed to Dr. Rexford S. Ahima, University of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 715 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104. Email: ahima{at}mail.med.upenn.edu

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