Obese mice lacking iNOS are sensitized to the metabolic actions of PPAR{gamma} agonism

doi:10.2337/db08-0540

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Original Research

Obese mice lacking iNOS are sensitized to the metabolic actions of PPAR ${gamma}$ 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 Peyot⁴, Martin G. Latour⁴, Julien Lamontagne⁴, Maria E. Trujillo⁵, Philipp E. Scherer^5,^,6, Marc Prentki⁴, Yves Deshaies^1,^,3, and André Marette^1,^,2

¹Department of Anatomy and Physiology, Laval University
²Lipid Research Unit, Laval University Hospital Research Center, and
³Laval Hospital Research Center, Québec, Québec, Canada
⁴Molecular 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
⁵Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
⁶Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, 75390-8549, USA

Objective: Synthetic ligands for peroxisome proliferator-activated receptor ${gamma}$ (PPAR ${gamma}$ ) improve insulin sensitivity in obesity but it is stillunclear if inflammatory signals modulate their metabolic actions.In this study we tested whether targeted disruption of iNOS,a key inflammatory mediator in obesity, modulates the metaboliceffects of rosiglitazone (RSG) in obese mice.

Research Design and Methods: iNOS^–/– and iNOS^+/+ were subjected to a high-fatdiet or standard diet for 18 weeks and were then treated withRSG for 2 weeks. Whole-body insulin sensitivity and glucosetolerance were determined and metabolic tissues harvested toassess activation of insulin and AMPK signaling pathways andthe levels of inflammatory mediators.

Results: RSG was found to similarly improve whole-body insulin sensitivityand insulin signaling to Akt/PKB in skeletal muscle of obeseiNOS^–/– and obese iNOS^+/+ mice. However, RSG furtherimproved glucose tolerance and liver insulin signaling onlyin obese mice lacking iNOS. This genotype-specific effect ofRSG on glucose tolerance was linked to a markedly increasedability of the drug to raise plasma adiponectin levels. Accordingly,RSG increased AMPK activation in muscle and liver only in obeseiNOS^–/– mice. PPAR ${gamma}$ transcriptional activity wasincreased in adipose tissue of iNOS^–/– mice. Conversely,treatment of 3T3-L1 adipocytes with a nitric oxide donor bluntedPPAR ${gamma}$ activity.

Conclusions: Our results identify the iNOS/NO pathway as a critical modulatorof PPAR ${gamma}$ activation and circulating adiponectin levels, and showthat invalidation of this key inflammatory mediator improvesthe efficacy of PPAR ${gamma}$ agonism in an animal model of obesity andinsulin resistance.

Correspondence: andre.marette{at}crchul.ulaval.ca