Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Veterans Administration Puget Sound Health Care System, Seattle, Washington 98108
Correspondence: Address all correspondence and requests for reprints to: David E. Cummings, M.D., Associate Professor of Medicine, University of Washington, Veterans Administration Puget Sound Health Care System, 1660 South Columbian Way, S-111-Endo, Seattle, Washington 98108. E-mail: davidec{at}u.washington.edu
The rising tide of obesity is one of the most pressing healthissues of our time, yet existing medicines to combat the problemare disappointingly limited in number and effectiveness. Fortunately,a recent burgeoning of mechanistic insights into the neuroendocrineregulation of body weight provides an expanding list of moleculartargets for novel, rationally designed antiobesity pharmaceuticals.In this review, we articulate a set of conceptual principlesthat we feel could help prioritize among these molecules inthe development of obesity therapeutics, based on an understandingof energy homeostasis. We focus primarily on central targets,highlighting selected strategies to stimulate endogenous catabolicsignals or inhibit anabolic signals. Examples of the formerapproach include methods to enhance central leptin signalingthrough intranasal leptin delivery, use of superpotent leptin-receptoragonists, and mechanisms to increase leptin sensitivity by manipulatingSOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by firstlosing weight with traditional interventions. Techniques toaugment signaling by neurochemical mediators of leptin actionthat lie downstream of at least some levels of obesity-associatedleptin resistance include activation of melanocortin receptorsor 5-HT2C and 5-HT1B receptors. We also describe strategiesto inhibit anabolic molecules, such as neuropeptide Y, melanin-concentratinghormone, ghrelin, and endocannabinoids. Modulation of gastrointestinalsatiation and hunger signals is discussed as well. As scientistscontinue to provide fundamental insights into the mechanismsgoverning body weight, the future looks bright for developmentof new and better antiobesity medications to be used with dietand exercise to facilitate substantial weight loss.
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