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Chronic Treatment with Sildenafil Improves Energy Balance and Insulin Action in High Fat-Fed Conscious Mice

¹Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
²Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
³Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27704 USA

Correspondence: julio.ayala{at}vanderbilt.edu

Stimulation of nitric oxide (NO)-guanosine 3',5'-cyclic monophosphate (cGMP) signaling results in vascular relaxation and increased muscle glucose uptake (MGU). We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 (PDE5) 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+L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, UCP-1 protein levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil+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 MGU 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+L-arginine did not improve insulin action. These results show that PDE5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.

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