The epigenetic recognizes our predisposition to obesity as the key assumption of the mismatch between the human genome molded over millions of generations (thrifty genotype) evolved for efficient food collection and fat deposition to survive periods of famine, now frugally coping with the modern dietary and physical environments of energy dense foods and/or sedentary lifestyle. Having fat as major energy-yielding substrate, the thriftiness to effectively detect, metabolize, and store fats likely provided tremendous selective advantages “(meat-adaptive genes)” to our ancestors. Among adipocytes, white-fat cells are specialized for the storage of chemical energy as triglycerides, a neutral non-toxic fat. Under excess of energy, adipocytes become enlarged and their secreted growth factors led neo-adipocyte to differentiate resulting hyperplasia. Leaked or broken open (hypertrophied) adipocytes are phagocytosed by resident and embed macrophages. Then, obesity-derived inflammatory stress is a systemic orchestrated metabolic network triggered by the chronic accumulation of lipids into adipose tissue. The resident macrophages amplify the inflammatory signal which is enhanced by the cross talk among endothelial cells (adhesion molecules), adipocytes (leptin), and resident macrophages, which together contribute to the production of pro-inflammatory cytokines resulting in the elevated circulating levels of insulin, leptin that accompany obesity. Differently from treating low-level targets by drugs (homeostatic model), the allostasis model has a more rational goal of intervention, the basis of Behavioral Medicine. As a model of Behavioral Medicine, our community-based ongoing epidemiological study, “Moving for Health Program” (1991 to 2019) with lifestyle re-education with supervised physical exercises and diet-counseling program, had promoted proactively, alternatively to homeostatic model, eutrophy and significant reductions of overweight-related NCDs with considerable economic impact on Health Care.