Collectively, our study unveils the beneficial effect of upregulating the HO system in the comorbidity of obesity and insulin resistance and suggests that the suppression of oxidative mediators, macrophage-M1-phenotype infiltration and extracellular matrix/remodeling proteins are among the multifaceted mechanisms by which the HO system maintains and enhances insulin signaling and counteract diabetic cardiomyopathy. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.