Details

Autor(en) / Beteiligte

• DALLAIRE, Patrice
• BELLMANN, Kerstin
• SCHERER, Philipp E
• PRENTKI, Marc
• DESHAIES, Yves
• MARETTE, André
• LAPLANTE, Mathieu
• GELINAS, Stephanie
• CENTENO-BAEZ, Carolina
• PENFORNIS, Patrice
• PEYOT, Marie-Line
• LATOUR, Martin G
• LAMONTAGNE, Julien
• TRUJILLO, Maria E

Titel

Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator–Activated Receptor-γ Agonism

Ist Teil von

• Diabetes (New York, N.Y.), 2008-08, Vol.57 (8), p.1999-2011

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2008

Quelle

Elektronische Zeitschriftenbibliothek - Freely accessible e-journals

Beschreibungen/Notizen

• Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator–Activated Receptor-γ Agonism Patrice Dallaire 1 2 , Kerstin Bellmann 1 2 , Mathieu Laplante 1 3 , Stéphanie Gélinas 1 2 , Carolina Centeno-Baez 1 2 , Patrice Penfornis 1 2 , Marie-Line Peyot 4 , Martin G. Latour 4 , Julien Lamontagne 4 , Maria E. Trujillo 5 , Philipp E. Scherer 5 6 , Marc Prentki 4 , Yves Deshaies 1 3 and André Marette 1 2 1 Department of Anatomy and Physiology, Laval University, Québec, Québec, Canada 2 Lipid Research Unit, Laval University Hospital Research Center, Québec, Québec, Canada 3 Laval Hospital Research Center, Québec, Québec, Canada 4 Molecular Nutrition Unit, Department of Nutrition and Biochemistry, University of Montreal and the Montreal Diabetes Research Centre, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada 5 Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 6 Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Corresponding author: Dr. André Marette, andre.marette{at}crchul.ulaval.ca Abstract OBJECTIVE— Synthetic ligands for peroxisome proliferator–activated receptor-γ (PPAR-γ) improve insulin sensitivity in obesity, but it is still unclear whether inflammatory signals modulate their metabolic actions. In this study, we tested whether targeted disruption of inducible nitric oxide (NO) synthase (iNOS), a key inflammatory mediator in obesity, modulates the metabolic effects of rosiglitazone in obese mice. RESEARCH DESIGN AND METHODS— iNOS −/− and iNOS +/+ were subjected to a high-fat diet or standard diet for 18 weeks and were then treated with rosiglitazone for 2 weeks. Whole-body insulin sensitivity and glucose tolerance were determined and metabolic tissues harvested to assess activation of insulin and AMP-activated protein kinase (AMPK) signaling pathways and the levels of inflammatory mediators. RESULTS— Rosiglitazone was found to similarly improve whole-body insulin sensitivity and insulin signaling to Akt/PKB in skeletal muscle of obese iNOS −/− and obese iNOS +/+ mice. However, rosiglitazone further improved glucose tolerance and liver insulin signaling only in obese mice lacking iNOS. This genotype-specific effect of rosiglitazone on glucose tolerance was linked to a markedly increased ability of the drug to raise plasma adiponectin levels. Accordingly, rosiglitazone increased AMPK activation in muscle and liver only in obese iNOS −/− mice. PPAR-γ transcriptional activity was increased in adipose tissue of iNOS −/− mice. Conversely, treatment of 3T3-L1 adipocytes with a NO donor blunted PPAR-γ activity. CONCLUSIONS— Our results identify the iNOS/NO pathway as a critical modulator of PPAR-γ activation and circulating adiponectin levels and show that invalidation of this key inflammatory mediator improves the efficacy of PPAR-γ agonism in an animal model of obesity and insulin resistance. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 5 May 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 29, 2008. Received April 22, 2008. DIABETES