Melanin-concentrating hormone as a therapeutic target

Among the worldwide population, the frequency of obesity has increased significantly over the last decade [1]. Approximately 30% of the current United States adult population is classified as obese [defined as a body mass index (BMI)>30], while an additional 30% of U.S. adults are overweight (BMI>25) [2]. Similar trends have also been observed in many industrialized countries, principally those adopting a western diet and sedentary lifestyle [3]. This epidemic is having a pronounced worldwide economic impact, with estimated annual direct and indirect costs of $117 billion in the U.S. alone [4]. Importantly, the ramifications of the obesity epidemic are not merely aesthetic or financial. Obese individuals have a significantly higher risk of mortality and related co-morbidities such as hyperlipidemia, cardiovascular disease, hypertension and Type 2 diabetes mellitus, as well as other health problems such as arthritis, sleep apnea and certain forms of cancer [1,5]. Approximately 47 million Americans are affected with metabolic syndrome (also termed Syndrome X, insulin resistance syndrome, Reaven syndrome or metabolic cardiovascular syndrome), which is defined as the clustering of obesity, insulin resistance, hypertension, and dyslipidemia [6]. Many affected individuals are at increased risk for developing Type 2 diabetes and mortality from cardiovascular disease [7,8]. As a first line of treatment for metabolic syndrome, the NCEP has suggested that weight reduction be primary focus, as this has been shown to reduce all risk factors of metabolic syndrome and delay or halt the development of Type 2 diabetes [9-11]. Maintaining weight loss solely by implementing changes in lifestyle remains difficult. Currently, two medications are approved for weight loss in the U.S.: orlistat (Xenical®), a pancreatic lipase inhibitor, and sibutramine (Meridia®), a serotonin and norepinepherine reuptake inhibitor. Both of these medications suffer from patient compliance issues and undesirable side effects which consequently limit their therapeutic potential. As a result, the search for antiobesity therapies with improved pharmacodynamic profiles has been a major focus within the pharmaceutical industry. Among the pharmacological targets, regulation of melanin-concentrating hormone (MCH) has emerged as increasing genetic and preclinical evidence has demonstrated that antagonism of the MCH 1-receptor may provide an effective therapy for the treatment of obesity and related co-morbidities. © 2005 Elsevier Inc. All rights reserved.