Physiology of weight regain: Lessons from the classic Minnesota Starvation Experiment on human body composition regulation

Since its publication in 1950, the Biology of Human Starvation, which describes the classic longitudinal Minnesota Experiment of semistarvation and refeeding in healthy young men, has been the undisputed source of scientific reference about the impact of long-term food deprivation on human physiology and behavior. It has been a guide in developing famine and refugee relief programs for international agencies, in exploring the effects of food deprivation on the cognitive and social functioning of those with anorexia nervosa and bulimia nervosa, and in gaining insights into metabolic adaptations that undermine obesity therapy and cachexia rehabilitation. In more recent decades, the application of a systems approach to the analysis of its data on longitudinal changes in body composition, basal metabolic rate, and food intake during the 24 weeks of semistarvation and 20 weeks of refeeding has provided rare insights into the multitude of control systems that govern the regulation of body composition during weight regain. These have underscored an internal (autoregulatory) control of lean-fat partitioning (highly sensitive to initial adiposity), which operates during weight loss and weight regain and revealed the existence of feedback loops between changes in body composition and the control of food intake and adaptive thermogenesis for the purpose of accelerating the recovery of fat mass and fat-free mass. This paper highlights the general features and design of this grueling experiment of simulated famine that has allowed the unmasking of fundamental control systems in human body composition autoregulation. The integration of its outcomes constitutes the "famine reactions" that drive the normal physiology of weight regain and obesity relapse and provides a mechanistic "autoregulation-based" explanation of how dieting and weight cycling, transition to sedentarity, or developmental programming may predispose to obesity. It also provides a system physiology framework for research toward elucidating proteinstatic and adipostatic mechanisms that control hunger-appetite and adaptive thermogenesis, with major implications for a better understanding (and management) of cachexia, obesity, and cardiometabolic diseases.