Drug development strategies for the treatment of obesity: How to ensure efficacy, safety, and sustainable weight loss

Drug Design, Development and Therapy

Volumn 8, Issue , 2014, Pages 2391-2400

  Barja Fernandez, S ^a,b,c   Leis, R ^b   Casanueva, F F ^b,c   Seoane, L M ^a,c  

^a Grupo Fisiopatología Endocrina   (Spain)

^b HOSPITAL CLÍNICO UNIVERSITARIO   (Spain)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

Energy balance; Obesity; Pharmacotherapy

Indexed keywords

1 (2,4 DICHLOROPHENYL) 5 (4 IODOPHENYL) 4 METHYL N MORPHOLINO 1H PYRAZOLE 3 CARBOXAMIDE; ADIPONECTIN; AGOUTI RELATED PROTEIN; AMFEBUTAMONE; AMFEBUTAMONE PLUS NALTREXONE; AMPHETAMINE; ANOREXIGENIC AGENT; ANTIOBESITY AGENT; CANNABINOID 1 RECEPTOR; CHOLECYSTOKININ; COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT PEPTIDE; DEXFENFLURAMINE; DIPEPTIDYL PEPTIDASE IV; FENFLURAMINE; FIBROBLAST GROWTH FACTOR 21; LIRAGLUTIDE; LORCASERIN; LY 2405319; METRELEPTIN; NALOXONE; NEUROPEPTIDE Y; OSTEOGENIC PROTEIN 1; PEPTIDE YY; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHENTERMINE; PHENTERMINE PLUS TOPIRAMATE; PROOPIOMELANOCORTIN; RIMONABANT; TETRAHYDROLIPSTATIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; PEPTIDE;

ADIPOGENESIS; ADIPOSE TISSUE; ARTICLE; BARIATRIC SURGERY; BEHAVIOR THERAPY; CARDIOVASCULAR DISEASE; CLINICAL EFFECTIVENESS; CONSTIPATION; DIET THERAPY; DRUG APPROVAL; DRUG DEPENDENCE; DRUG SAFETY; DRUG TARGETING; ELEVATED BLOOD PRESSURE; EMOTIONAL DISORDER; ENERGY BALANCE; ENERGY EXPENDITURE; FAT MASS; FOOD INTAKE; GASTROINTESTINAL TRACT FUNCTION; HOMEOSTASIS; HUMAN; HYPOTHALAMUS; INSOMNIA; LIFESTYLE MODIFICATION; LIPODYSTROPHY; LIPOGENESIS; LUNG DISEASE; METABOLIC REGULATION; NONHUMAN; OBESITY; PROTEIN INTERACTION; PROTEIN LOCALIZATION; RESTLESSNESS; TACHYCARDIA; THERMOGENESIS; TREATMENT PLANNING; WEIGHT REDUCTION; XEROSTOMIA; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; SAFETY;

ANTI-OBESITY AGENTS; DRUG DISCOVERY; OBESITY; PEPTIDES; SAFETY; WEIGHT LOSS;

EID: 84919400550     PISSN: None     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S53129     Document Type: Article

References (77)

1. World Health Organization. The SuRF Report 2. Geneva, Switzerland: World Health Organization, 2005.
2. Wang Y, Beydoun MA. The obesity epidemic in the United States– gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007;29:6–28.
3. Rodgers RJ, Tschop MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Model Mech. 2012;5:621–626.
4. Carotenuto M, Bruni O, Santoro N, et al. Waist circumference predicts the occurrence of sleep-disordered breathing in obese children and adolescents: a questionnaire-based study. Sleep Med. 2006;7: 357–361.
5. Carotenuto M, Santoro N, Grandone A, et al. The insulin gene variable number of tandemrepeats (INS VNTR) genotype and sleep disordered breathing in childhood obesity. J Endocrinol Invest. 2009;32:752–755.
6. World Health Organization. Obesity: Preventing and Managing the Global Epidemic (WHO/NUT/NCD/98.1). Geneva, Switzerland: World Health Organization, 1997.
7. O'Dea K. Overview of the thrifty genotype hypothesis. Asia Pac J Clin Nutr. 1995;4:339–340.
8. Kopelman PG. Obesity as a medical problem. Nature. 2000;404: 635–643.
9. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187–193.
10. Haslam DW, James WP. Obesity. Lancet. 2005;366:1197–1209.
11. Esposito M, Antinolfi L, Gallai B, et al. Executive dysfunction in children affected by obstructive sleep apnea syndrome: an observational study. Neuropsychiatr Dis Treat. 2013;9:1087–1094.
12. Carotenuto M, Esposito M, Parisi L, et al. Depressive symptoms and childhood sleep apnea syndrome. Neuropsychiatr Dis Treat.2012;8: 369–373.
13. Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298:2028–2037.
14. Kushner RF. Weight loss strategies for treatment of obesity. Prog Cardiovasc Dis. 2014;56:465–472.
15. Verrotti A, Carotenuto M, Altieri L, et al. Migraine and obesity: metabolic parameters and response to a weight loss programme. Pediatr Obes. Epub 2014 July 3.
16. Verrotti A, Agostinelli S, D'Egidio C, et al. Impact of a weight loss program on migraine in obese adolescents. Eur J Neurol. 2013;20: 394–397.
17. Sharma AM, Padwal R. Obesity is a sign–over-eating is a symptom: an aetiological framework for the assessment and management of obesity. Obes Rev. 2010;11:362–370.
18. Dieguez C, Vazquez MJ, Romero A, Lopez M, Nogueiras R. Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins. Neuroendocrinology. 2011;94:1–11.
19. Hnasko TS, Szczypka MS, Alaynick WA, During MJ, Palmiter RD. A role for dopamine in feeding responses produced by orexigenic agents. Brain Res. 2004;1023:309–318.
20. Cawley EI, Park S, aan het Rot M, et al. Dopamine and light: dissecting effects on mood and motivational states in women with subsyn-dromal seasonal affective disorder. J Psychiatry Neurosci. 2013;38: 388–397.
21. Singh M. Mood, food, and obesity. Front Psychol. 2014;5:925.
22. Lage R, Dieguez C, Vidal-Puig A, Lopez M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med. 2008;14:539–549.
23. Guyenet SJ, Schwartz MW. Clinical review. Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab. 2012;97:745–755.
24. Bluher M. Clinical relevance of adipokines. Diabetes Metab J. 2012;36:317–327.
25. Seoane LM, Lopez M, Tovar S, et al. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology. 2003;144:544–551.
26. Turer AT, Scherer PE. Adiponectin: mechanistic insights and clinical implications. Diabetologia. 2012;55:2319–2326.
27. Sell H, Bluher M, Kloting N, et al. Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care. 2013; 36:4083–4090.
28. Kloting N, Fasshauer M, Dietrich A, et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab. 2010;299:E506–E515.
29. Oh IS, Shimizu H, Satoh T, et al. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443:709–712.
30. Kloting N, Kovacs P, Kern M, et al. Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects. Diabetologia.2011;54:1819–1823.
31. Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013; 18:333–340.
32. Fisher FM, Kleiner S, Douris N, et al. FGF21 regulates PGC-lalpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26:271–281.
33. Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009; 20:98–105.
34. Tseng YH, Kokkotou E, Schulz TJ, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454:1000–1004.
35. Townsend KL, Suzuki R, Huang TL, et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J. 2012;26:2187–2196.
36. Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–468.
37. Roca-Rivada A, Castelao C, Senin LL, et al. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One. 2013;8:e60563.
38. Raschke S, Elsen M, Gassenhuber H, et al. Evidence against a beneficial effect of irisin in humans. PLoS One. 2013;8:e73680.
39. Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene? Nature.2012;488:E9–E10; discussion E10–E11.
40. Neary MT, Batterham RL. Gut hormones: implications for the treatment of obesity. Pharmacol Ther. 2009;124:44–56.
41. Folgueira C, Seoane LM, Casanueva FF. The brain-stomach connection. Front Horm Res. 2014;42:83–92.
42. Inui A, Asakawa A, Bowers CY, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004;18:439–456.
43. Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117:13–23.
44. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660.
45. Seoane LM, Al-Massadi O, Barreiro F, Dieguez C, Casanueva FF. Growth hormone and somatostatin directly inhibit gastric ghrelin secretion. An in vitro organ culture system. J Endocrinol Invest. 2007; 30:RC22–RC25.
46. Zhang X, Li W, Li P, et al. Intraportal infusion of ghrelin could inhibit glucose-stimulated GLP-1 secretion by enteric neural net in Wistar rat. Biomed Res Int. 2014;2014:923564.
47. Garcia-Galiano D, Tena-Sempere M. Emerging roles of NUCB2/ nesfatin-1 in the metabolic control of reproduction. Curr Pharm Des. 2013;19:6966–6972.
48. Cota D, Marsicano G, Lutz B, et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord. 2003;27: 289–301.
49. Pazos MR, Tolon RM, Benito C, et al. Cannabinoid CB1 receptors are expressed by parietal cells of the human gastric mucosa. J Histochem Cytochem. 2008;56:511–516.
50. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology. 2005;146:1473–1481.
51. Senin LL, Al-Massadi O, Folgueira C, et al. The gastric CB1 receptor modulates ghrelin production through the mTOR pathway to regulate food intake. PLoS One. 2013;8:e80339.
52. Li Z, Xu G, Li Y, et al. mTOR-dependent modulation of gastric nesfatin-1/NUCB2. Cell Physiol Biochem. 2012;29:493–500.
53. United States Department of Health and Human Services. United States. Department of Agriculture. Dietary Guidelines Advisory Committee. Dietary Guidelines for Americans, 2010. Washington, DC: Government Printing Office, 2010, xi, 95.
54. Jakicic JM. The effect of physical activity on body weight. Obesity (Silver Spring). 2009; 17(Suppl 3):S34–S38.
55. Kral JG, Naslund E. Surgical treatment of obesity. Nat Clin Pract Endocrinol Metab. 2007;3:574–583.
56. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741–752.
57. Lopez M, Seoane LM, Tovar S, et al. Orexin-A regulates growth hormone-releasing hormone mRNA content in a nucleus-specific manner and somatostatin mRNA content in a growth hormone-dependent fashion in the rat hypothalamus. Eur J Neurosci. 2004;19:2080–2088.
58. Ioannides-Demos LL, Proietto J, McNeil JJ. Pharmacotherapy for obesity. Drugs. 2005;65:1391–1418.
59. Bai B, Wang Y. The use of lorcaserin in the management of obesity: a critical appraisal. Drug Des Devel Ther. 2010;5:1–7.
60. Kirilly E, Gonda X, Bagdy G. CB1 receptor antagonists: new discoveries leading to new perspectives. Acta Physiol (Oxf). 2012;205:41–60.
61. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311:74–86.
62. Bluher M. Adipokines–removing road blocks to obesity and diabetes therapy. Mol Metab. 2014;3:230–240.
63. Bauche IB, El Mkadem SA, Pottier AM, et al. Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation. Endocrinology. 2007;148:1539–1549.
64. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem.2003;278:2461–2468.
65. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–437.
66. Savage DB, O'Rahilly S. Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest. 2002;109:1285–1286.
67. Foo JP, Mantzoros CS. Leptin in congenital or HIV-associated lipodystrophy and metabolic syndrome: a need for more mechanistic studies and large, randomized, placebo-controlled trials. Metabolism. 2012;61:1331–1336.
68. Chou K, Perry CM. Metreleptin: first global approval. Drugs. 2013;73: 989–997.
69. Muller TD, Sullivan LM, Habegger K, et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J Pept Sci. 2012;18:383–393.
70. Okamoto Y, Folco EJ, Minami M, et al. Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. Circ Res. 2008; 102: 218–225.
71. Kusminski CM, Scherer PE. The road from discovery to clinic: adiponectin as a biomarker of metabolic status. Clin Pharmacol Ther. 2009;86:592–595.
72. Heiker JT, Kloting N, Kovacs P, et al. Vaspin inhibits kallikrein 7 by serpin mechanism. Cell Mol Life Sci. 2013;70:2569–2583.
73. Lotfy M, Singh J, Kalasz H, Tekes K, Adeghate E. Medicinal Chemistry and Applications of Incretins and DPP-4 Inhibitors in the Treatment of Type 2 Diabetes Mellitus. Open Med Chem J. 2011;5:82–92.
74. Saito M, Okamatsu-Ogura Y, Matsushita M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009;58:1526–1531.
75. Al-Massadi O, Pardo M, Casanueva FF, Seoane LM. The stomach as an energy homeostasis regulating center. An approach for obesity. Recent Pat Endocr Metab Immune Drug Discovery. 2010;4:75–84.
76. Kim GW, Lin JE, Biomain ES, Waldman SA. Antiobesity pharmacotherapy: new drugs and emerging targets. Clin Pharmacol Ther. 2014;95:53–66.
77. Ravussin E, Gautier JF. Metabolic predictors of weight gain. Int J Obes Relat Metab Disord. 1999;23(Suppl 1):37–41.