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. Here, INS is linked to diabetic cardiomyopathy.