Pharm Res (2011) 28:1792–1818 DOI 10.1007/s11095-010-0341-1 EXPERT REVIEW Current and Future Drug Targets in Weight Management Renger F. Witkamp Received: 25 August 2010 / Accepted: 29 November 2010 / Published online: 23 December 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com ABSTRACT Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbid- ity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed. KEY WORDS energy metabolism . food-intake . obesity complications . satiety hormones . weight management R. F. Witkamp (*) Division of Human Nutrition Wageningen University P.O. Box 8129, 6700 EV Wageningen, The Netherlands e-mail: renger.witkamp@wur.nl ABBREVIATIONS 5-HT serotonin (5-hydroxytryptamine) 11β-HSD1 11-β hydroxysteroid dehydrogenase type 1 AgRP agouti-related protein β3AR β3-adrenoceptors BAT brown adipose tissue BMI body mass index CART cocaine-amphetamine-regulated transcript CB1 cannabinoid receptor type 1 CCK cholecystokinin CNS central nervous system DGAT diacylglycerol O-acyltransferase DPP-IV dipeptidyl peptidase IV EEC entero-endocrine cell GABA gamma-amino butyrate GH growth hormone GI gastro-intestinal GLP-1 glucagon-like peptide 1 HPA(-axis) hypothalamic–pituitary–adrenal (-axis) MCH melanine-concentrating hormone MGAT 2-acylglycerol O-acyltransferase MSH melanocyte-stimulating hormone MTP microsomal triglyceride transfer protein NPY neuropeptide Y OXM oxyntomodulin POMC pro-opiomelanocortin PP pancreatic polypeptide PPAR γ peroxisome proliferator-activated receptor-γ PYY peptide YY SGLT2 (low affinity) sodium-dependent glucose co-transporter TRPV type 1 transient receptor potential cation channel V type 1