The emerging science of body weight regulation and its impact on obesity treatment (2003)

Obesity is a complex disorder characterized by the accumulation of excess adipose tissue.While obesity has long been considered a behavioral disorder, discovery of the hormone leptin in 1994 catalyzed the field of obesity research by demonstrating the existence of an afferent humoral signal from adipose tissue to the central nervous system.Current evidence suggests that once adipose tissue accumulates, a system of overlapping neuroendocrine systems prevents it from diminishing.This counter-regulatory mechanism, which has probably evolved as protection against starvation and fetal or neonatal wastage, causes changes in appetite and metabolism that make volitional weight loss difficult to achieve.Obesity is defined in terms of BMI, calculated as weight (kg)/[height (m)] 2 .Although a continuous variable, BMI has been categorized based on epidemiologic data to denote the relative risk of developing comorbid conditions.A BMI less than 25 is considered to be normal, 25-29.9 is overweight, and greater than or equal to 30, obese.Data from the 1999 National Health Nutritional and Exercise survey demonstrated that 34% of adults in the United States were overweight, and 30.8% obese, resulting in a total of 64.8% above normal weight.The prevalence of overweight and obesity in children was 13%, a doubling since 1980, while adolescents have experienced a tripling in prevalence since then.Being overweight or obese substantially increases the risk of morbidity from a number of conditions, including type 2 diabetes mellitus (DM), hypertension, dyslipidemia, coronary heart disease, congestive heart failure, stroke, gallbladder disease, hepatic steatosis, osteoarthritis, sleep apnea, and endometrial, breast, prostate, and colon cancers.An increase in all-cause mortality is also associated with higher body weights.Adipose tissue is an active endocrine organ that produces free fatty acids and hormones, such as IL-6, TNF-, plasminogen activation inhibitor-1, angiotensinogen, and others, directly related to the insulin resistance, hyperlipidemia, inflammation, thrombosis, and hypertension that characterize obesity.Visceral fat appears to be the greatest contributor to these effects, probably because of its location in the portal circulation draining to the liver. Regulation of energy homeostasisThe discovery of leptin and other genes responsible for obesity in rodents has had a considerable impact on our understanding of body weight regulation.Leptin (derived from Greek leptos, meaning thin) is a hormone that is produced by fat cells and circulates at levels proportional to body fat content.Leptin crosses the bloodbrain barrier to bind to its receptor in the hypothalamus, thereby activating signals that inhibit food intake and increase energy expenditure.When leptin is given to leptin-deficient mice, obesity and metabolic abnormalities such as hyperglycemia, hyperinsulinemia, and hypercortisolemia are reversed.However, the initial hypothesis that human obesity results from a deficiency in leptin has not been upheld.In fact, most obese humans have high circulating concentrations of leptin, and only a few individuals with severe obesity have been identified either with congenital leptin deficiency or a mutation in the gene encoding the leptin receptor (Table 1).In early clinical trials, high doses of subcutaneously-administered leptin, resulting in greater than 20-fold increases in circulating leptin concentrations, were often associated with reactions at the injection site and had only a modest effect in reducing body weight.Therefore, it has been suggested that obese persons are leptin resistant.If indeed a defect in the leptin pathway gives rise to human obesity, it may be due to a postreceptor defect in the transduction of leptin signaling