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

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

Abbreviations: 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

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.

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