title: Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice.
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 x kg(-1) x 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 2200 Pierce Ave., 702 Light Hall, Nashville, TN 37232, USA. julio.ayala@vanderbilt.edu
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Julien
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Rottman
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000821:Animal Feed; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D004041:Dietary Fats; D004452:Echocardiography; D004734:Energy Metabolism / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D015309:Glucose Clamp Technique; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D001120:Arginine; D000068677:Sildenafil Citrate