Leptin as a therapeutic agent—trials and tribulations

CS Mantzoros, JS Flier - The Journal of Clinical Endocrinology & …, 2000 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2000academic.oup.com
Obesity is a prevalent condition that is reaching epidemic proportions in the United States.
Sixty-three percent of men and 55% of women are overweight [body mass index (BMI) of 25
kg/m2 or higher], whereas 22% of the United States adult population is obese (BMI of 30
kg/m2 or higher)(1). More importantly, the prevalence of obesity has almost doubled in the
past decade (1). The consequences of obesity are serious. Approximately 80% of obese
adults have at least one and 40% have two or more comorbidities, which include diabetes …
Obesity is a prevalent condition that is reaching epidemic proportions in the United States. Sixty-three percent of men and 55% of women are overweight [body mass index (BMI) of 25 kg/m2 or higher], whereas 22% of the United States adult population is obese (BMI of 30 kg/m2 or higher)(1). More importantly, the prevalence of obesity has almost doubled in the past decade (1). The consequences of obesity are serious. Approximately 80% of obese adults have at least one and 40% have two or more comorbidities, which include diabetes, hyperlipidemia, hypertension, cardiovascular disease, gallbladder disease, osteoarthritis, and certain cancers (1, 2). The number of deaths directly attributable to obesity, approximately 300,000 annually in the United States, is second only to smoking in its contribution to total mortality rates (2). The direct and indirect costs of obesity have been estimated to account for 10% of the national health care budget. Thus, it is evident that obesity is a major medical and public health problem.
Obesity results from storage of excess energy as fat during periods when energy intake exceeds energy expenditure. Our understanding of the specific mechanisms underlying the regulation of energy homeostasis has been greatly advanced by research that followed the discovery of leptin 5 yr ago (3–5). Leptin, the product of the ob gene, is mainly produced by adipocytes, and its circulating levels reflect the amount of energy stored in adipose tissue (3–5). Although body fat accounts for approximately 50–60% of leptin’s variability, other factors such as age, gender, diurnal variation, and hormonal (mainly insulin) and cytokine levels also contribute to the regulation of leptin levels. Leptin acts by binding to specific receptors and activating the JAK STAT system for signal transduction (reviewed in Refs. 3 and 4). Leptin has pleiotropic actions, but its main target is considered to be the central nervous system. In the hypothalamus, leptin increases energy expenditure and inhibits appetite and weight gain by decreasing the expression of orexigenic neuropeptides such as NPY and AgRP, and by increasing the expression of anorexigenic neuropeptides such as a-MSH, CRH, and CART (reviewed in Refs. 3–5). The discovery of leptin 5 yr ago triggered renewed enthusiasm for obesity research and has reinforced the view that obesity is a disease with strong biological basis. It has also accelerated research aimed at delineating the molecular pathways regulating energy homeostasis.
Oxford University Press