Abstract

Objective: We hypothesized that the induction of heme oxygenase-1 (HO-1) and increased HO activity, which induces arterial anti-oxidative 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 administered (intraperitoneally) the HO-1 inducer CoPP (3 mg/kg) with and without the HO inhibitor SnMP (2 mg/100g) 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 were isolated and assessed for HO expression and adipogenesis.

Results: HO activity was reduced in ob mice compared to 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 p<0.01 respectively compared to vehicle animals), increased serum adiponectin and decreased plasma TNFα, 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 as well as in cultured mesenchymal stem cells, and increased adiponectin levels in the culture media. Inhibition of HO activity decreased adiponectin and increased secretion of TNFα, 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.