Chronic Carbon Monoxide Treatment Attenuates Development of Obesity and Remodels Adipocytes in Mice Fed a High Fat Diet

OBJECTIVE: Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high fat diet. DESIGN: Experiments were performed on C57BL/6J mice fed a high (60%) fat diet from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, CORM-A1 (5 mg/kg, ip every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O(2) consumption, CO(2) production, activity, and body heat production were measured at 28 weeks after start of the experimental protocol. RESULTS: Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM-A1 treatment in mice fed a high fat diet resulted in significant decreases in fasted blood glucose, insulin, and body fat and increased O(2) consumption, and heat production as compared to mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF1, PGC-1α, and UCP-1 protein levels in epidydmal fat. CONCLUSION: Our results demonstrate that chronic CO treatment prevents the development of high fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes.