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(Hypertension. 2009;53:508.)
© 2009 American Heart Association, Inc.

Original Articles

Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats

Angelique Nicolai; Ming Li; Dong Hyun Kim; Stephen J. Peterson; Luca Vanella; Vincenzo Positano; Amalia Gastaldelli; Rita Rezzani; Luigi F. Rodella; George Drummond; Claudia Kusmic; Antonio L'Abbate; Attallah Kappas; Nader G. Abraham

From the Departments of Pharmacology (A.N., M.L., D.H.K., S.J.P., L.V., G.D., N.G.A.) and Medicine (S.J.P., N.G.A.), New York Medical College, Valhalla; Scuola Superiore Sant’Anna and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology (V.P., A.G., C.K., A.L.), Pisa, Italy; University of Brescia (R.R., L.F.R.), Italy; and Rockefeller University (A.K.), New York.

Correspondence to Dr Nader G. Abraham, Professor of Pharmacology and Medicine, Department of Pharmacology, New York Medical College, Valhalla, NY 10595 or Dr Attallah Kappas, Rockefeller University, New York, NY 10021. E-mail nader_abraham{at}nymc.edu

Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean–CoPP, ZDF, and ZDF–CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF–CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.

Key Words: insulin resistance • heme oxygenase-1 • adiponectin • adiposity • endocannabinoid • pAMPK

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