Chronic HO-1 Induction with Cobalt Protoporphyrin (CoPP) Treatment Increases Oxygen Consumption, Activity, Heat Production and Lowers Body Weight in Obese Melanocortin-4 Receptor Deficient Mice

OBJECTIVE: Heme oxygenase-1 induction (HO-1) elicits chronic weight loss in several rodent models of obesity. Despite these findings, the mechanism by which HO-1 induction reduces body weight is unclear. Chronic HO-1 induction does not alter food intake suggesting other mechanisms such as increases in metabolism and activity may be responsible for the observed reduction of body weight. In this study, we investigated the mechanism of weight loss elicited by chronic HO-1 induction in a model of genetic obesity due to melanocortin-4 receptor (MC4R) deficiency. DESIGN: Experiments were performed on loxTB MC4R deficient mice as well as lean controls. Mice were administered cobalt protoporphyrin (CoPP, 5 mg/kg), an inducer of HO-1, once weekly from 4 to 23 weeks of age. Body weights were measured weekly and fasted blood glucose and insulin as well as food intake were determined at 18 weeks of age. O(2) consumption, CO(2) production, activity, and body heat production were measured at 20 weeks of age. RESULTS: Chronic CoPP treatment resulted in a significant decrease in body weight from 5 weeks on in loxTB mice. Chronic CoPP treatment resulted in a significant decrease in fasted blood glucose levels, plasma insulin, and a significant increase in plasma adiponectin levels in MC4R deficient mice. Chronic CoPP treatment increased O(2) consumption (47 ± 4 vs. 38 ± 3 ml/kg/min, P<0.05) and CO(2) production (44 ± 7 vs. 34 ± 4 ml/kg/min, P<0.05) in treated versus non-treated, MC4R deficient mice (n=4). Heat production (10%) and activity (18%) were also significantly (P<0.05) increased in CoPP treated MC4R deficient mice. CONCLUSION: Our results suggest that chronic HO-1 induction with CoPP induction elicits weight loss by increasing metabolism and activity by an MC4R independent pathway.