Emerging therapeutic strategies for obesity

Endocrine Reviews

Volumn 27, Issue 7, 2006, Pages 779-793

  Foster Schubert, Karen E ^a   Cummings, David E ^a,b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AC 162352; AMYLIN; ANTIOBESITY AGENT; CANNABINOID RECEPTOR ANTAGONIST; CILIARY NEUROTROPHIC FACTOR; DEXFENFLURAMINE; ENDOCANNABINOID; FENFLURAMINE; GHRELIN; GLUCAGON LIKE PEPTIDE 1; HORMONE ANTAGONIST; HORMONE RECEPTOR STIMULATING AGENT; LEPTIN; MELANIN CONCENTRATING HORMONE; MELANOTAN 2; N ACETYL ALPHA INTERMEDIN[4-10]CYCLO[4 NORLEUCINE 5 ASPARTIC ACID 7 [3 (2 NAPHTHYL)ALANINE] 10 LYSINAMIDE]; NEUROPEPTIDE Y; OXYNTOMODULIN; PEPTIDE YY; PLACEBO; PRAMLINTIDE; PROTEIN TYROSINE PHOSPHATASE 1B; RECOMBINANT CILIARY NEUROTROPHIC FACTOR; RIMONABANT; SEROTONIN 1B AGONIST; SEROTONIN 2C AGONIST; SEROTONIN AGONIST; SIBUTRAMINE; SUPPRESSOR OF CYTOKINE SIGNALING 3; UNINDEXED DRUG;

ANXIETY; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DEPRESSION; DIABETES MELLITUS; DIET THERAPY; DOSE RESPONSE; DRUG MECHANISM; DRUG POTENTIATION; DRUG RESEARCH; DRUG SAFETY; DRUG TOLERABILITY; DRUG TRANSPORT; DRUG WITHDRAWAL; ENERGY BALANCE; ERECTILE DYSFUNCTION; FOOD INTAKE; HUMAN; LOW DRUG DOSE; NAUSEA; NEUROENDOCRINE SYSTEM; NONHUMAN; OBESITY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; SATIETY; SIDE EFFECT; TREATMENT PLANNING; WEIGHT REDUCTION;

ANTI-OBESITY AGENTS; BODY WEIGHT; EATING; GASTROINTESTINAL HORMONES; HUMANS; LEPTIN; METABOLISM; NEUROPEPTIDES; NEUROSECRETORY SYSTEMS; OBESITY; RECEPTORS, CANNABINOID;

EID: 33845588762     PISSN: 0163769X     EISSN: 0163769X     Source Type: Journal    
DOI: 10.1210/er.2006-0041     Document Type: Review

References (121)

1. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM 2006 Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295:1549-1555
2. 1998 Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. The Evidence Report. National Institutes of Health. Obes Res 6(Suppl 2):51S-209S
3. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC 2005 Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 142:532-546
4. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW 2006 Central nervous system control of food intake and body weight. Nature 443:289-295
5. Flier JS 2004 Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337-350
6. Leibel RL, Rosenbaum M, Hirsch J 1995 Changes in energy expenditure resulting from altered body weight. N Engl J Med 332:621-628
7. Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel RL 2003 Is the energy homeostasis system inherently biased toward weight gain? Diabetes 52:232-238
8. Cummings D, Overduin J, Gastrointestinal regulation of food intake. J Clin Invest, in press
9. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK 2004 Aging in rhesus monkeys: relevance to human health interventions. Science 305:1423-1426
10. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E 2006 Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295:1539-1548
11. Himms-Hagen J 2004 Exercise in a pill: feasibility of energy expenditure targets. Curr Drug Targets CNS Neurol Disord 3:389-409
12. Bray GA, Greenway FL 1999 Current and potential drugs for treatment of obesity. Endocr Rev 20:805-875
13. Cummings DE, Foster-Schubert KE, Overduin J 2005 Ghrelin and energy balance: focus on current controversies. Curr Drug Targets 6:153-169
14. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R 2006 The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73-100
15. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS 1998 Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182-3194
16. Gavrilova O, Marcus-Samuels B, Leon LR, Vinson C, Reitman ML 2000 Leptin and diabetes in lipoatrophic mice. Nature 403:850
17. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578
18. Handschin C, Spiegelman BM 2006 Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27:728-735
19. Trujillo ME, Scherer PE 2006 Adipose tissue-derived factors: impact on health and disease. Endocr Rev 27:762-778
20. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L, Bouchard C 2006 The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14:529-644
21. Farooqi IS, O'Rahilly S 2006 Genetics of obesity in humans. Endocr Rev 27:710-718
22. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-431
23. Farooqi I, Jebb S, Langmack G, Lawrence E, Cheetham C, Prentice A, Hughes IA, McCamish M, O'Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879-884
24. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M 1999 Recombinant leptin for weight loss in obese and lean adults. JAMA 282:1568-1575
25. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL 2005 Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 115:3579-3586
26. Boozer CN, Leibel RL, Love RJ, Cha MC, Aronne LJ 2001 Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats. Metabolism 50:889-893
27. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte Jr D 1996 Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2:589-593
28. Fliedner S, Schulz C, Lehnert H 2006 Brain uptake of intranasally applied radioiodinated leptin in Wistar rats. Endocrinology 147:2088-2094
29. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS 2000 Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105:1827-1832
30. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263-1271
31. Peelman F, Couturier C, Dam J, Zabeau L, Tavernier J, Jockers R 2006 Techniques: new pharmacological perspectives for the leptin receptor. Trends Pharmacol Sci 27:218-225
32. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS 1998 Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1:619-625
33. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, Tremblay ML 2002 Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2:497-503
34. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG 2002 PTP-1B regulates leptin signal transduction in vivo. Dev Cell 2:489-495
35. Wang MY, Orci L, Ravazzola M, Unger RH 2005 Fat storage in adipocytes requires inactivation of leptin's paracrine activity: implications for treatment of human obesity. Proc Natl Acad Sci USA 102:18011-18016
36. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A 2004 Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10:739-743
37. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS 2004 Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10:734-738
38. Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN 1999 SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98:617-627
39. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP 1999 Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544-1548
40. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB 2006 Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12:917-924
41. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB 2000 Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479-5489
42. Cone RD 2006 Studies on the physiological functions of the melanocortin system. Endocr Rev 27:736-749
43. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661-671
44. Yaswen L, Diehl N, Brennam M, Hochgeschwender V 1999 Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5:1066-1070
45. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155-157
46. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, Challis BG, O'Rahilly S 2006 Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55:2549-2553
47. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S 1997 Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303-306
48. Lloyd DJ, Bohan S, Gekakis N 2006 Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 15:1884-1893
49. Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V, Ghoussaini M, Wachter C, Hercberg S, Charpentier G, Patsch W, Pattou F, Charles MA, Tounian P, Clement K, Jouret B, Weill J, Maddux BA, Goldfine ID, Walley A, Boutin P, Dina C, Froguel P 2005 Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 37:863-867
50. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141
51. Vaisse C, Clement K, Guy-Grand B, Froguel P 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113-114
52. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S 1998 A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111-112
53. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P 2000 Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253-262
54. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S 2003 Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085-1095
55. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH 2000 Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:97-102
56. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD 2000 A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141:3518-3521
57. Feng N, Young SF, Aguilera G, Puricelli E, Adler-Wailes DC, Sebring NG, Yanovski JA 2005 Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 54:2663-2667
58. Fan W, Boston B, Kesterson R, Hruby V, Cone R 1997 Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165-168
59. Madison LD, Marks DL 2006 Anticatabolic properties of melanocortin-4 receptor antagonists. Curr Opin Clin Nutr Metab Care 9:196-200
60. Jobst EE, Enriori PJ, Sinnayah P, Cowley MA 2006 Hypothalamic regulatory pathways and potential obesity treatment targets. Endocrine 29:33-48
61. Palatin Technologies web page with press release describing their clinical trial of melanocortin receptor agonists. http://www. palatin.com/news/news.asp?ID=163
62. Baskin DG 2006 Single-minded view of melanocortin signaling in energy homeostasis. Endocrinology 147:4539-4541
63. Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Levy E, Mitchell GA, Himms-Hagen J, Fan CM 2001 Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 10:1465-1473
64. Kublaoui BM, Holder Jr JL, Gemelli T, Zinn AR 2006 Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. Mol Endocrinol 20:2483-2492
65. Holder JL, Butte NF, Zinn AR 2000 Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:101-108
66. Kublaoui BM, Holder Jr JL, Tolson KP, Gemelli T, Zinn AR 2006 SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake. Endocrinology 147:4542-4549
67. Yang C, Gagnon D, Vachon P, Tremblay A, Levy E, Massie B, Michaud JL 2006 Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake. J Neurosci 26:7116-7120
68. ALS CNTF Treatment Study Group 1996 A double-blind placebocontrolled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 46:1244-1249
69. Xu B, Dube MG, Kalra PS, Farmerie WG, Kaibara A, Moldawer LL, Martin D, Kalra SP 1998 Anorectic effects of the cytokine, ciliary neurotropic factor, are mediated by hypothalamic neuropeptide Y: comparison with leptin. Endocrinology 139:466-473
70. Gloaguen I, Costa P, Demartis A, Lazzaro D, Di Marco A, Graziani R, Paonessa G, Chen F, Rosenblum CI, Van der Ploeg LH, Cortese R, Ciliberto G, Laufer R 1997 Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc Natl Acad Sci USA 94:6456-6461
71. Anderson KD, Lambert PD, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ 2003 Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice. J Neuroendocrinol 15:649-660
72. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL, Burn P, Palmiter RD 1999 Response of melanocortin-4-deficient mice to anorectic and orexigenic peptides. Nat Genet 21:119-122
73. Kokoeva MV, Yin H, Flier JS 2005 Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310:679-683
74. Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, Heshka S, Vicary C, Guler HP 2003 Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 289:1826-1832
75. Regeneron Pharmaceuticals press release regarding their Axokine Phase III program for the treatment of obesity. http://www. regeneron.com/investor/ press_detail.asp?v_c_id=169
76. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D 1995 Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542-546
77. Nonogaki K, Strack AM, Dallman MF, Tecott LH 1998 Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4:1152-1156
78. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK 2002 Activation of central melanocortin pathways by fenfluramine. Science 297:609-611
79. Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, Liu HY, Zigman JM, Balthasar N, Kishi T, Lee CE, Aschkenasi CJ, Zhang CY, Yu J, Boss O, Mountjoy KG, Clifton PG, Lowell BB, Friedman JM, Horvath T, Butler AA, Elmquist JK, Cowley MA 2006 Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51:239-249
80. Sargent PA, Sharpley AL, Williams C, Goodall EM, Cowen PJ 1997 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology (Berl) 133:309-312
81. Smith S, Prosser W, Donahue D, Anderson, C, Shanahan W 2006 APD356, an orally-active selective 5-HT2C agonist, reduces body weight in obese adult men and women. American Diabetes Association 66th Scientific Sessions, Washington DC; Abstract 344-OR
82. Erickson JC, Clegg KE, Palmiter RD 1996 Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381:415-421
83. Erickson JC, Hollopeter G, Palmiter RD 1996 Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274:1704-1707
84. Feletou M, Galizzi JP, Levens NR 2006 NPY receptors as drug targets for the central regulation of body weight. CNS Neurol Disord Drug Targets 5:263-274
85. Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil DJ, Van der Ploeg LH, Ishii Y, Okabe T, Fukami T, Ihara M 2000 L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist. Biochem Biophys Res Commun 272:169-173
86. Polidori C, Ciccocioppo R, Regoli D, Massi M 2000 Neuropeptide Y receptor(s) mediating feeding in the rat: characterization with antagonists. Peptides 21:29-35
87. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD 1998 Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med 4:718-721
88. Soll RM, Dinger MC, Lundell I, Larhammer D, Beck-Sickinger AG 2001 Novel analogues of neuropeptide Y with a preference for the Y1-receptor. Eur J Biochem 268:2828-2837
89. Mullins D, Kirby D, Hwa J, Guzzi M, Rivier J, Parker E 2001 Identification of potent and selective neuropeptide Y Y(1) receptor agonists with orexigenic activity in vivo. Mol Pharmacol 60:534-540
90. Pedrazzini T, Seydoux J, Kunstner P, Aubert J, Grouzmann E, Beermann F, Brunner H 1998 Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med 4:722-726
91. Sainsbury A, Schwarzer C, Couzens M, Jenkins A, Oakes SR, Ormandy CJ, Herzog H 2002 Y4 receptor knockout rescues fertility in ob/ob mice. Genes Dev 16:1077-1088
92. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, Lowell B, Flier JS, Maratos-Flier E 2001 Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest 107:379-386
93. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E 1998 Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396:670-674
94. Pissios P, Bradley RL, Maratos-Flier E 2006 Expanding the scales: the multiple roles of MCH in regulating energy balance and other biological functions. Endocr Rev 27:606-620
95. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, Jiang MM, Feng Y, Camacho RE, Shen Z, Frazier EG, Yu H, Metzger JM, Kuca SJ, Shearman LP, Gopal-Truter S, MacNeil DJ, Strack AM, MacIntyre DE, Van der Ploeg LH, Qian S 2002 Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA 99:3240-3245
96. Halford JC 2006 Obesity drugs in clinical development. Curr Opin Investig Drugs 7:312-318
97. West DB, Fey D, Woods SC 1984 Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 246:R776-R787
98. Murphy KG, Dhillo WS, Bloom SR 2006 Gut peptides in the regulation of food intake and energy homeostasis. Endocr Rev 27:719-727
99. Henry RR, Ratner RE, Stonehouse AH, Guan X, Poon T, Malone JK, Kim DD, Kendall DM 2006 Exenatide maintained glycemic control with associated weight reduction over 2 years in patients with type 2 diabetes. American Diabetes Association 66th Scientific Sessions, Washington DC; Abstract 485P
100. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR 2002 Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418:650-654
101. Tschop M, Castaneda TR, Joost HG, Thone-Reineke C, Ortmann S, Klaus S, Hagan MM, Chandler PC, Oswald KD, Benoit SC, Seeley RJ, Kinzig KP, Moran TH, Beck-sickinger AG, Koglin N, Rodgers RJ, Blundell JE, Ishii Y, Beattie AH, Holch P, Allison DB, Raun K, Madsen K, Wulff BS, Stidsen CE, Birringer M, Kreuzer OJ, Schindler M, Arndt K, Rudolf K, Mark M, Deng XY, Whitcomb DC, Halem H, Taylor J, Dong J, Datta R, Culler M, Craney S, Flora D, Smiley D, Heiman ML 2004 Physiology: does gut hormone PYY3-36 decrease food intake in rodents? Nature 430:1 p following 165; discussion, 2 p following 165
102. Moran TH, Smedh U, Kinzig KP, Scott KA, Knipp S, Ladenheim EE 2005 Peptide YY(3-36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am J Physiol Regul Integr Comp Physiol 288:R384-R388
103. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR 2003 Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 349:941-948
104. Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR 2003 Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 88:4696-4701
105. Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR 2005 Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 54:2390-2395
106. Schmitz O, Brock B, Rungby J 2004 Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 53(Suppl 3):S233-S238
107. Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG, Weyer C 2004 Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res 12:661-668
108. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS 2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714-1719
109. Drazen DL, Vahl TP, D'Alessio DA, Seeley RJ, Woods SC 2006 Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 147:23-30
110. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW 2005 Absence of ghrelin protects against early-onset obesity. J Clin Invest 115:3573-3578
111. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK 2005 Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115:3564-3572
112. Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD 2006 Vaccination against weight gain. Proc Natl Acad Sci USA 103:13226-13231
113. Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, Wang L, Klussmann S, Macintyre DE, Howard AD, Strack AM 2006 Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology 147:1517-1526
114. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI 1990 Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561-564
115. Di Marzo V, Bifulco M, De Petrocellis L 2004 The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771-784
116. Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, et al 1994 SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240-244
117. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U 2003 The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423-431
118. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P 2004 CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 28:640-648
119. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S 2005 Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389-1397
120. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J 2006 Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761-775
121. Despres JP, Golay A, Sjostrom L 2005 Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121-2134