Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat–Fed Conscious Mice

Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat–Fed Conscious Mice Julio E. Ayala 1 , Deanna P. Bracy 1 , Brianna M. Julien 1 , Jeffrey N. Rottman 2 , Patrick T. Fueger 3 and David H. Wasserman 1 1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 2 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina Address correspondence and reprint requests to Julio E. Ayala, PhD, Vanderbilt University Medical Center, 2200 Pierce Ave., 702 Light Hall, Nashville, TN 37232. E-mail: julio.ayala{at}vanderbilt.edu Abstract Stimulation of nitric oxide–cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat–fed mice treated with sildenafil plus l -arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus l -arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l -arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU · kg −1 · min −1 )–euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat–fed mice with sildenafil plus l -arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance. 2[14C]DG, 2[14C]deoxyglucose 2[14C]DGP, 2[14C]DG-6-phosphate eNOS, endothelial NO synthase FFA, free fatty acid GIR, glucose infusion rate IRS, insulin receptor substrate PI, phosphatidylinositol UCP, uncoupling protein VDAC, voltage-dependent anion channel Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 17 January 2007. DOI: 10.2337/db06-0883. The costs of