| Mediobasal Hypothalamic Sirtuin 1 Is Essential for Resveratrol's Effects on Insulin Action in Rats. | |
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MedLine Citation:
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PMID: 21896928 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVESirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.RESEARCH DESIGN AND METHODSSD (Charles River Laboratories International, Inc., Wilmington, MA) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin (sh)RNA, inhibited the hypothalamic ATP-sensitive potassium (K(ATP)) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.RESULTSOur studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.CONCLUSIONSTaken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action. |
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Authors:
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Colette M Knight; Roger Gutierrez-Juarez; Tony K T Lam; Isabel Arrieta-Cruz; Loli Huang; Gary Schwartz; Nir Barzilai; Luciano Rossetti |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-6 |
Journal Detail:
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Title: Diabetes Volume: - ISSN: 1939-327X ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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