The (dys)regulation of energy storage in obesity

Metabolic energy stored mainly as adipose tissue is homeostatically regulated. There is strong evidence that human body weight (BW) is physiologically regulated, i.e., maintained within a relatively narrow range in most mammals, including humans. Nevertheless, the prevalence of obesity has increased markedly in recent decades and now constitutes major medical and socioeconomic problems worldwide. This review focuses on understanding this paradox and the clinical issues that it has spawned: how and why do individuals become obese and how can we help those with obesity lose excess BW and body fat and maintain whatever loss they achieve? Excess BW gain occurs when physiological responses that usually resist short-term weight gain fail to compensate for excess caloric intake occurring over extended periods of time, often over many years or even decades. On the other hand, the difficulties of achieving BW loss and maintenance of reduced BW in obese subjects are due, in part, to the operation of the same physiological regulatory system that helps maintain a healthy BW in individuals without obesity. However, given obesity's association with many pathological conditions, we maintain that the physiological processes that resist BW loss and persistently drive regain are examples of dysregulation. Here we review research in humans and animals addressing these and other unresolved issues in the physiology of obesity. We bring important unresolved problems into focus and, in some cases, propose hypotheses that can further elucidate their mechanisms to provide research opportunities into modalities that might lead to more effective treatments of obesity.