Obesity is a consequence of the complex interplay between genetics and environment. Several studies have shown that body weight is maintained at a stable range, known as the "set-point," despite the variability in energy intake and expenditure. Additionally, it has been shown that the body is more efficient protecting against weight loss during caloric deprivation compared to conditions of weight gain with overfeeding, suggesting an adaptive role of protection during periods of low food intake. Emerging evidence on bariatric surgery outcomes, particularly gastric bypass, suggests a novel role of these surgical procedures in establishing a new set-point by alterations in body weight regulatory physiology, therefore resulting in sustainable weight loss results. Continuing research is necessary to elucidate the biological mechanisms responsible for this change, which may offer new options for the global burden of obesity.