Combating Obesity by Targeting Nuclear Receptors

Obesity is emerging as the main health threat of the 21st century. According to the CDC 65% of all individuals in the U. S. are overweight or obese. Mortality increases exponentially with increasing BMI; the grossly obese (BMI>40) have three times the death rate of “ideal” weight individuals. Obese individuals are also twice as likely to have diabetes and three times as likely to be hypertensive. A 16-year study has shown that obesity accounted for 14-20 % of all cancer deaths. It has been demonstrated that even modest (10%) reduction in body weight, can ameliorate or prevent the onset of these pathologies. It is estimated that obesity associated annual health cost exceeds $70 billion. Currently available therapies include a centrally acting appetite suppressant (Meridia®) and an inhibitor of fat absorption (Xenical®). There are a number of clinical and pre-clinical activities ongoing with anti-obesity drugs. Most of those drugs target 7 Transmembrane G-Protein Coupled Receptors (7TM GPCR's) such as Melanocortin-4 Receptor (MC4R), Melanin Concentrating Hormone (MCH), Cholecystokinine-1 Receptor (CCK-1R), Cannabinoid-1 Receptor (CB-1), 5HydroxyTryptamine 2c Receptor (5HT2c), Histamine-3 Receptor (H-3R). With the exponential increase of newly discovered nuclear receptors, this class is quickly becoming one of the most important targets for drug discovery. Emerging knowledge about the genetics of nuclear receptors is pointing strongly toward the important role that they play in metabolic control. In addition recent experimental data in animals models demonstrate that modulation of various nuclear receptors can result in reduction in weight gain and / or weight loss.