Adiponectin is a beneficial hormone produced primarily by adipocytes. Paradoxically, circulating adiponectin levels are reduced in the context of obesity and associated diseases. This hypoadiponectinemia is implicated in the aetiology of obesity-related cardiometabolic diseases making therapeutic strategies to increase adiponectin attractive. An emerging body of literature suggests that increasing heme oxygenase 1 (HO-1) may increase adiponectin levels, prompting the proposal of an ‘HO-1 – adiponectin axis’. We have performed a series of investigations to explore this possibility.
Using two in vitro models of human adipocytes, combined with a comprehensive array of pharmaceutical (cobalt protoporphyrin (CoPP) or hemin) and genetic modulators of HO-1, we found that neither acute1 nor chronic induction of HO-1 results in increased adiponectin production. However, in a mouse model of diet-induced obesity we observed that systemic induction of HO-1 with CoPP increased circulating adiponectin levels and this was concurrent with decreased food intake, body weight gain and adipocyte size as well as enhanced insulin sensitivity and reduced liver steatosis. Importantly only the effect on adiponectin was blunted when mice were co-treated with an inhibitor of HO-1 activity (SnMP).
Taken together, our in vitro and in vivo observations suggest that CoPP increases circulating adiponectin levels in an indirect manner that is, at least partly, dependent on HO-1 activity. Furthermore, our in vivo studies indicate that systemic treatment with CoPP results in reduced food intake and improvements in a range of metabolic parameters in a manner that is independent of HO-1 activity. Further studies are warranted to identify the underlying mechanisms that may reveal new molecular targets for the treatment of obesity and associated diseases.
1M. Yang et al, Mol Cell Endocrinol. 2015, 15;413:209-16.