Adiponectin is a salutary hormone produced by adipocytes, and hypoadiponectinemia is implicated in the aetiology of obesity-related cardiometabolic diseases, making therapeutic strategies to increase adiponectin attractive. Emerging evidence, predominantly from preclinical studies, suggests induction of HO-1 increases adiponectin production, and improves obesity-related metabolic dysfunction. This has stimulated considerable interest in HO-1 inducing agents for the treatment of metabolic syndrome in humans. We have recently established that induction of HO-1 in mature human adipocytes in vitro does not increase adiponectin production, which argues against a direct HO-1 – adiponectin axis1. We have now undertaken a study in a preclinical model of diet-induced obesity, to determine the effect of induction of HO-1 in vivo on adiponectin and other metabolic parameters under obesogenic conditions.
Wildtype male mice were fed a high fat diet for 18 weeks, prior to the administration of the HO-1 inducer cobalt protoporphyrin (CoPP, 3 mg/kg/week) for a further 6 weeks. CoPP treatment resulted in increased HO-1 expression in the liver and adipose tissue, and concurrently reduced food intake, reduced weight gain, increased both total and HMW (the most metabolically active form) adiponectin and dramatically increased insulin sensitivity. Consistent with these findings, CoPP treatment profoundly improved liver steatosis in obese mice. Conversely, despite reducing adipocyte size in epididymal adipose tissue, CoPP treatment increased the expression of pro-inflammatory and infiltration markers (Mcp-1, Il-6, Tnfa and Cd68).
Our results demonstrate that induction of HO-1 with CoPP reduces food intake and leads to improvements in circulating adiponectin levels, insulin sensitivity and liver steatosis in a preclinical model of obesity. These improvements occur despite a deterioration of adipose tissue inflammatory tone. Collectively, these findings suggest that HO-1 selectively improves metabolic parameters in obese mice, and may hold promise as a therapeutic for the treatment of obesity and obesity-related disease.