Mediobasal Hypothalamic SIRT1 Is Essential for Resveratrol’s Effects on Insulin Action in Rats
| Autor: | Colette M. Knight, Gary J. Schwartz, Isabel Arrieta-Cruz, Tony K.T. Lam, Roger Gutierrez-Juarez, Nir Barzilai, Loli Huang, Luciano Rossetti |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Biology Resveratrol Glibenclamide 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Internal medicine Internal Medicine medicine Glucose homeostasis 030304 developmental biology 0303 health sciences Sirtuin 1 Insulin food and beverages medicine.disease Endocrinology chemistry Hypothalamus Systemic administration biology.protein hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Diabetes. 60:2691-2700 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE Sirtuin 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 METHODS Sprague Dawley (SD) 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 RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (KATP) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally. RESULTS Our 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 KATP 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. CONCLUSIONS Taken 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. |
| Databáze: | OpenAIRE |
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