It is shown that environmental factors, e.g., high-fat diet and lack of physical activity, not only promote the onset of obesity but lead to impairment of the action of adiponectin and its receptors, thus accounting in part for the onset of insulin resistance, type 2 diabetes/metabolic syndrome, and atherosclerosis in modern society. Here, ADIPOQ is linked to obesity due to melanocortin 4 receptor deficiency.