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Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

¹ Department of Pharmacology, New York Medical College, Valhalla, New York
² Department of Medicine, New York Medical College, Valhalla, New York
³ Department of Biomedical Science, Division of Anatomy, University of Brescia, Brescia, Italy
⁴ Department of Cardiology, New York Medical College, Valhalla, New York
⁵ First Department of Pathology, Kansai Medical University, Moriguchi, Osaka, Japan

Corresponding author: Dr. Nader G. Abraham, Professor of Pharmacology and Medicine, New York Medical College, Valhalla, NY 10595. E-mail: nader_abraham{at}nymc.edu

Abbreviations: CFU-F, colony forming units–fibroblasts; CoPP, cobalt protoporphyrin; FBS, fetal bovine serum; GCMS, gas chromatography–mass spectrometry; HO, heme oxygenase; IL, interleukin; MSC, mesenchymal stem cell; PPAR, peroxisome proliferator–activated receptor; ROS, reactive oxygen species; SnMP, stannous mesoporphyrin; TNF-, tumor necrosis factor-

OBJECTIVE—We hypothesized that the induction of heme oxygenase (HO)-1 and increased HO activity, which induces arterial antioxidative enzymes and vasoprotection in a mouse and a rat model of diabetes, would ameliorate insulin resistance, obesity, and diabetes in the ob mouse model of type 2 diabetes.

RESEARCH DESIGN AND METHODS—Lean and ob mice were intraperitoneally administered the HO-1 inducer cobalt protoporphyrin (3 mg/kg CoPP) with and without the HO inhibitor stannous mesoporphyrin (2 mg/100 g SnMP) once a week for 6 weeks. Body weight, blood glucose, and serum cytokines and adiponectin were measured. Aorta, adipose tissue, bone marrow, and mesenchymal stem cells (MSCs) were isolated and assessed for HO expression and adipogenesis.

RESULTS—HO activity was reduced in ob mice compared with age-matched lean mice. Administration of CoPP caused a sustained increase in HO-1 protein, prevented weight gain, decreased visceral and subcutaneous fat content (P < 0.03 and 0.01, respectively, compared with vehicle animals), increased serum adiponectin, and decreased plasma tumor necrosis factor- (TNF-), interleukin (IL)-6, and IL-1β levels (P < 0.05). HO-1 induction improved insulin sensitivity and glucose tolerance and decreased insulin levels. Upregulation of HO-1 decreased adipogenesis in bone marrow in vivo and in cultured MSCs and increased adiponectin levels in the culture media. Inhibition of HO activity decreased adiponectin and increased secretion of TNF-, IL-6, and IL-1β levels in ob mice.

CONCLUSIONS—This study provides strong evidence for the existence of an HO-1–adiponectin regulatory axis that can be manipulated to ameliorate the deleterious effects of obesity and the metabolic syndrome associated with cardiovascular disease and diabetes.

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