Article Summary Medical Consequences of Obesity. Bray GA. J Clin Endocrinol Metab. 2004;89:2583-2589. Objective: To review the effects of obesity on morbidity and mortality. Observation: Diabetes mellitus is the fifth leading cause of death in the US and results in $132 billion annually in direct and indirect costs. Excess weight has been associated with increased risk of diabetes mellitus, osteoarthritis, hypertension, cardiovascular disease, gallbladder disease, psychosocial dysfunction, and some forms of cancer. Each risk factor can be classified into 1 of 2 pathophysiologies: arising from the physiology of the increased fat mass or arising from metabolic changes that are associated with excess fat. Fat cells and adipose tissue may be viewed as types of endocrine cells and an endocrine gland, respectively. Hypertrophy and hyperplasia are the pathologic lesions of this endocrine organ in patients who are obese. Enlarged fat cells increase secretion of free fatty acids (FFA) and peptides, including adipsin, complement D, and, specifically, leptin. The last is the component that secures the role of the adipocyte as an endocrine cell and fat as an endocrine organ. However, from the perspective of pathophysiology, release of FFA is the most important. Increased visceral fat enhances the degree of insulin resistance that is associated with obesity and hyperinsulinemia; increased insulin secretion and insulin resistance are a result of obesity. Diabetes mellitus is strongly associated with severe obesity in men and women in all ethnic groups, with the risk increasing according to the degree and duration of obesity, and particularly to an increase in adipose tissue. Studies reviewed in this paper indicate that as body mass index (BMI) increases, the relative risk of type 2 diabetes rises exponentially. Conclusion: It is estimated that between 280,000 and 325,000 deaths occur each year as a result of obesity and associated risk factors. Because obesity increases the risk of mortality, intentional weight loss would logically reduce this risk.