Current and Future Drug Targets in Weight Management 35. Couzin J. Medicine: bypassing medicine to treat diabetes. Science. 2008;320:438–40. 36. Rothman RB, Baumann MH. Appetite suppressants, cardiac valve disease and combination pharmacotherapy. Am J Ther. 2009;16:354–64. 37. Witkamp RF. Biologically active compounds in food products and their effects on obesity and diabetes. Comprehensive natural products II. Oxford: Elsevier; 2010. p. 509–45. 38. Birari RB, Bhutani KK. Pancreatic lipase inhibitors from natural sources: unexplored potential. Drug Discov Today. 2007;12:879–89. 39. FDA. Early communication about an ongoing safety review Orlistat (marketed as Alli and Xenical). 2009. http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandPro viders/DrugSafetyInformationforHeathcareProfessionals/ ucm179166. 40. Kopelman P, De Groot GH, Rissanen A, et al. Weight loss, HbA 1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (xenical). Obesity. 2010;18:108–15. 41. Hussain MM, Bakillah A. New approaches to target microsomal triglyceride transfer protein. Curr Opin Lipidol. 2008;19:572–8. 42. Van Gaal L, Vercruysse F, Wajs E, Xie J, Ways D, van Nueten L. JNJ-16269110, an enterically targetted microsomal triglycer- ide transfer protein inhibitor, lowers body weight in overweight/ obese subjects. Obes Rev. 2010;11(supplement s1):42. 43. Chen HC, Farese Jr RV. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:482–6. 44. Shi YG, Cheng D. Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Am J Physiol Endocrinol Metab. 2009;297:E10–8. 45. AstraZeneca. Pipepline summary 2010; http://www.astraze neca.com/research/our-pipeline-summary/. Access date August 15, 2010. 46. Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diab Obes Metab. 2009;11:79–88. 47. Johnson & Johnson. Pharmaceutical pipeline - recent approvals/ potential filings. Selective highlights as of 7/20/2010. http:// files.shareholder.com/downloads/JNJ/990821560x0x387659/ f0fa5052-2cba-4402-91ab-b40b1fbd5e76/Q22010pipeline.pdf. 48. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–3. 49. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31. 50. Thuny F, Richet H, Casalta J-P, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS ONE. 2010;5:e9074. 51. Engelstoft MS, Egerod KL, Holst B, Schwartz TW. A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab. 2008;8:447–9. 52. Delzenne N, Blundell J, Brouns F, et al. Gastrointestinal targets of appetite regulation in humans: ILSI Supplement. Obes Rev. 2010;11:234–50. 53. Torres SJ, Nowson CA. Relationship between stress, eating behavior, and obesity. Nutrition. 2007;23:887–94. 54. Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117:13–23. 55. Obici S. Molecular targets for obesity therapy in the brain. Endocrinology. 2009;150:2512–7. 56. Neary MT, Batterham RL. Gut hormones: implications for the treatment of obesity. Pharmacol Ther. 2009;124:44–56. 57. Yan KS, Pasricha PJ. Acting in good taste: nutrient sensors in the gut. Gut. 2009;58:897–8. 1815 58. Young RL, Sutherland K, Pezos N, et al. Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes. Gut. 2009;58:337–46. 59. Yoshida R, Ohkuri T, Jyotaki M, et al. Endocannabinoids selectively enhance sweet taste. Proc Natl Acad Sci. 2010;107:935–9. 60. Cox HM, Tough IR, Woolston A-M, et al. Peptide YY is critical for acylethanolamine receptor GPR119-induced activation of gastrointestinal mucosal responses. Cell Metab. 2010;11:532–42. 61. Alpers DH. Nutrient sensing in de gastrointestinal tract. Curr Opin Gastroenterol. 2010;26:134–9. 62. Hansen HS, Diep TA. N-acylethanolamines, anandamide and food intake. Biochem Pharmacol. 2009;78:553–60. 63. Izzo AA, Sharkey KA. Cannabinoids and the gut: new develop- ments and emerging concepts. Pharmacol Ther. 2010;126:21– 38. 64. Lan H, Vassileva G, Corona A, et al. GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis. J Endocrinol. 2009;201:219–30. 65. Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes. 2009;58:1058–66. 66. Yang Y, Chen M, Georgeson KE, Harmon CM. Mechanism of oleoylethanolamide on fatty acid uptake in small intestine after food intake and body weight reduction. Am J Physiol Regul Integr Comp Physiol. 2007;292:R235–41. 67. Overton HA, Babbs AJ, Doel SM, et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006;3:167–75. 68. Fyfe MCT, Overton HA, Procter MJ, Reynet C, White JR. Chapter 9: new nonpeptide-binding GPCRs as targets for diabetes and the metabolic syndrome. Annu Rep Med Chem. 2007;129–45. 69. Overton HA, Fyfe MCT, Reynet C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol. 2008;153:S76–81. 70. Jones RM, Leonard JN, John EM. Chapter 7 the emergence of GPR119 agonists as anti-diabetic agents. Annual Reports in Medicinal Chemistry: Academic Press; 2009:149–70. 71. Semple G, Fioravanti B, Pereira G, et al. Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J Med Chem. 2008;51:5172–5. 72. Wu Y, Kuntz JD, Carpenter AJ, et al. 2, 5-Disubstituted pyridines as potent GPR119 agonists. Bioorg Med Chem Lett. 2010;20:2577–81. 73. Arena Pharmaceuticals. APD597 for type 2 diabetes. Accessed August 20, 2010. http://www.arenapharm.com/apd597.aspx? p=2.6. 74. Metabolex. Metabolex and Sanofi-Aventis enter into an agree- ment for novel type2 diabetes treatment. Accessed August 10, 2010. http://www.metabolex.com/news/jun252010.html. 75. Cota D. The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity. J Neuroendocrinol. 2008;20:35–8. 76. Di Marzo V, Després JP. CB1 antagonists for obesity; what lessons have we learned from rimonabant? Nat Rev Endocrinol. 2009;5:633–8. 77. Piazza PV, Lafontan M, Girard J. Integrated physiology and pathophysiology of CB1-mediated effects of the endocannabi- noid system. Diabetes Metabol. 2007;33:97–107. 78. Jones D. End of the line for cannabinoid receptor 1 as an anti- obesity target? Nat Rev Drug Discov. 2008;7:961–2. 79. Bermudez-Silva FJ, Viveros MP, McPartland JM, Rodriguez de Fonseca F. The endocannabinoid system, eating behavior and