Is Obesity or Adiposity-Based Chronic Disease Curable: The Set Point Theory, the Environment, and Second-Generation Medications

Adiposity-based chronic disease (ABCD) requires life-long treatment and follow up. Obesity protects obesity through altered regulation of caloric intake and set point mechanisms, which help maintain a high equilibrium body weight. Lifestyle interventions and obesity medications do not permanently alter the set point, which often makes weight loss achieved using lifestyle changes short-lived and operates to drive weight regain once medications are discontinued. Bariatric surgery procedures can alter appetite and lower the "set point" for the equilibrium body weight via unknown mechanisms. However, few patients attain an ideal body weight following surgery, many regain weight, and all require long-term follow up for the disease. The excess adiposity associated with ABCD gives rise to complications that impair health and confer morbidity and mortality; however, the genetic risks and potential interactions between genes and the environment that give rise to complications cannot be eliminated. The equilibrium body weight around which set point mechanisms operate can be modified by the environment, which underscores the importance of a less obesogenic environment for the prevention and treatment of ABCD on a population basis. Whether ABCD will eventually be curable will depend on a clear understanding of the molecular mechanisms that determine the set point regulation of body weight and the ability to permanently modulate the set point to oscillate around a lean body mass. However, the conceptualization of ABCD as a chronic disease does present us with opportunities for primary, secondary, and tertiary prevention to avert disease progression. For tertiary care, the advent of new, more effective second-generation obesity medications will allow clinicians to treat to target via active management of body weight into a target range that will ameliorate specific complications.