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 Ͻ 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-1␤ levels (P Ͻ 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-1␤ 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. Diabetes 57:1526-1535, 2008

We hypothesized that the apolipoprotein mimetic peptide L-4F, which induces arterial anti-oxidative enzymes and is vasoprotective in a rat model of diabetes, would ameliorate insulin resistance and diabetes in obese mice. L-4F (2 mg/kg/d) administered to ob/ob mice for 6 weeks limited weight gain without altering food intake, decreased visceral (P , 0.02) and subcutaneous (P , 0.045) fat content, decreased plasma IL-1b and IL-6 levels (P , 0.05) and increased insulin sensitivity, resulting in decreased glucose (P , 0.001) and insulin (P , 0.036) levels. In addition, L-4F treatment increased aortic and bone marrow heme oxygenase (HO) activity and decreased aortic and bone marrow superoxide production (P , 0.001). L-4F treatment increased serum adiponectin levels (P , 0.037) and decreased adipogenesis in mouse bone marrow (P , 0.039) and in cultures of human bone marrow-derived mesenchymal stem cells (P , 0.022). This was manifested by reduced adiposity, improved insulin sensitivity, improved glucose tolerance, increased plasma adiponectin levels, and reduced IL-1b and IL-6 levels in obese mice. This study highlights the existence of a temporal relationship between HO-1 and adiponectin that is positively affected by L-4F in the ob/ob mouse model of diabetes, resulting in the amelioration of the deleterious effects of diabetes.-Peterson,

Background-Apolipoprotein A1 mimetic peptide, synthesized from D-amino acid (D-4F), enhances the ability of HDL to protect LDL against oxidation in atherosclerotic animals. Methods and Results-We investigated the mechanisms by which D-4F provides antioxidant effects in a diabetic model.Sprague-Dawley rats developed diabetes with administration of streptozotocin (STZ). We examined the effects of daily D-4F (100 g/100 g of body weight, intraperitoneal injection) on superoxide (O 2 Ϫ ), extracellular superoxide dismutase (EC-SOD), vascular heme oxygenase (HO-1 and HO-2) levels, and circulating endothelial cells in diabetic rats. In response to D-4F, both the quantity and activity of HO-1 were increased. O 2 Ϫ levels were elevated in diabetic rats (74.8Ϯ8ϫ10 3 cpm/10 mg protein) compared with controls (38.1Ϯ8ϫ10 3 cpm/10 mg protein; PϽ0.01). D-4F decreased O 2 Ϫ levels to 13.23Ϯ1ϫ10 3 (PϽ0.05 compared with untreated diabetics). The average number of circulating endothelial cells was higher in diabetics (50Ϯ6 cells/mL) than in controls (5Ϯ1 cells/mL) and was significantly decreased in diabetics treated with D-4F (20Ϯ3 cells/mL; PϽ0.005). D-4F also decreased endothelial cell fragmentation in diabetic rats. The impaired relaxation typical of blood vessels in diabetic rats was prevented by administration of D-4F (85.0Ϯ2.0% relaxation). Western blot analysis showed decreased EC-SOD in the diabetic rats, whereas D-4F restored the EC-SOD level. Conclusions-We conclude that an increase in circulating endothelial cell sloughing, superoxide anion, and vasoconstriction in diabetic rats can be prevented by administration of D-4F, which is associated with an increase in 2 antioxidant proteins, HO-1 and EC-SOD.

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.