HO-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, and Isoprostane Levels in Mice Fed High Fructose Diets

Figure 9

Schematic diagram of fructose-mediated adipocyte expansion and potential mechanisms underlying HO-1-mediated improvement of fructose-induced adipocyte hypertrophy. Excessive fructose consumption is accompanied by decreases in HO-1 gene expression and a concurrent increase in cellular heme levels. Increase in cellular heme results in lipid peroxidation of the essential fatty acid, arachidonic acid, via activation of ROS. The metabolite of this process is isoprostane and, therefore, heme catalyzes isoprostane synthesis. Isoprostane release induces adipocyte hypertrophy and dysfunction. In contrast, the increase in HO-1 expression and HO activity by pharmacological agents, for example, CoPP, leads to a decrease in the cellular heme pool and an increase in the canonical Wnt pathway and of adiponectin. Adiponectin enhances the antioxidant mechanisms, thereby decreasing lipid droplet size along with attenuation of isoprostane production. An increase in HO activity lowers lipid peroxidation, thereby decreasing isoprostane production and diminishing expression of the adipogenic markers Peg-1/Mest, FAS, and aP2, resulting in the lowering of adipocyte hypertrophy. Thus, activation of the HO-1-adiponectin axis along with an increase in the canonical Wnt cascade results in decreased heme (prooxidant) levels and isoprostane production in adipocytes and a decrease in fructose-mediated adipocyte dysfunction and lipid accumulation.