Captopril normalizes insulin signaling and insulin-regulated substrate metabolism in obese (ob/ob) mouse hearts.
The goal of this study was to determine whether inhibiting the renin-angiotensin system would restore insulin signaling and normalize substrate use in hearts from obese ob/ob mice. Mice were treated for 4 wk with Captopril (4 mg/kg x d). Circulating levels of free fatty acids, triglycerides, and insulin were measured and glucose tolerance tests performed. Rates of palmitate oxidation and glycolysis, oxygen consumption, and cardiac power were determined in isolated working hearts in the presence and absence of insulin, along with levels of phosphorylation of Akt and AMP-activated protein kinase (AMPK). Captopril treatment did not correct the hyperinsulinemia or impaired glucose tolerance in ob/ob mice. Rates of fatty acid oxidation were increased and glycolysis decreased in ob/ob hearts, and insulin did not modulate substrate use in hearts of ob/ob mice and did not increase Akt phosphorylation. Captopril restored the ability of insulin to regulate fatty acid oxidation and glycolysis in hearts of ob/ob mice, possibly by increasing Akt phosphorylation. Moreover, AMPK phosphorylation, which was increased in hearts of ob/ob mice, was normalized by Captopril treatment, suggesting that in addition to restoring insulin sensitivity, Captopril treatment improved myocardial energetics. Thus, angiotensin-converting enzyme inhibitors restore the responsiveness of ob/ob mouse hearts to insulin and normalizes AMPK activity independently of effects on systemic metabolic homeostasis.
Tabbi-Anneni
Imene
I
Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Buchanan
Jonathan
J
Cooksey
Robert C
RC
Abel
E Dale
ED
D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D009924:Organ Culture Techniques; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000959:Antihypertensive Agents; D007328:Insulin; D000804:Angiotensin II; D002216:Captopril; D005947:Glucose