Current and Future Drug Targets in Weight Management INTRODUCTION—HEALTH RISKS OF BODY FAT Obesity has become a serious and worldwide public health problem with important consequences for healthcare costs (1–3). The common way to classify obesity is by body mass index (BMI), which is calculated as weight in kg/height in meters squared. Persons with a BMI over 25 are called overweight, whereas a BMI of over 30 represents obesity. Both classifications are major risk factors for a cluster of health complications often referred to as the metabolic syndrome (1,4,5). These include (pre-)diabetes type 2, hypertension and other cardiovascular complications. In addition, obesity leads to an elevated risk for developing other diseases, such as non-alcoholic fatty liver disease, osteoarthritis, sleep apnea, cognitive decline and certain forms of cancer (6). Although BMI remains a useful general indicator for health risk, particularly at a population level, it has become clear that health complications are largely dependent on the localization and activity of the different fat depots. For any given amount of total body fat, those individuals with a predominant excess of intra-abdominal 1793 or visceral adipose tissue are at substantially higher risk of becoming insulin resistant or getting any of the other features of the metabolic syndrome (4,7,8). Therefore, waist circumference or waist/hip ratio is often a better indicator than BMI (9,10). Furthermore, there remains a risk of under diagnosis, since persons who look “thin outside” but have relatively much fat “hidden” within organs, such as muscles, heart and liver (“fat inside”), bear considerable health risks (11,12). Within fat tissue, the adipocyte phenotypes and infiltration of immune cells are considered pivotal determinants for the development of metabolic complications (13,14). It has been shown that adipose tissue can initiate and maintain a low-grade inflammatory process, which in turn activates inflammatory responses in liver and other organs. Another important risk factor is the presence of high levels of free fatty acids in plasma (15,16). Taken together, it is understandable that the problem of adiposity has boosted considerable activity in pharmaceu- tical development, which is often going far beyond achieving or maintaining a healthy body weight only. Fig. 1 illustrates the great diversity in potential targets. Fig. 1 Schematic representation of potential strategies and targets as discussed in this review, to reduce food intake, body weight or adipose tissue mass.