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01.07.2000 | Leading Article

Promising New Approaches to the Management of Obesity

verfasst von: Ilse L. Mertens, Dr Luc F. Van Gaal

Erschienen in: Drugs | Ausgabe 1/2000

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Abstract

The pathophysiology of obesity is complex with many different pathways involved. A better understanding of these weight-regulating mechanisms has lead to the identification of new targets for anti-obesity agents. Most attention has been given to the centrally acting neuropeptides regulating food intake. Leptin, playing a key-role, exerts its action through several neuropeptides such as neuropeptide Y, α-melanocyte stimulating hormone and agouti related protein. Cocaine-and amphetamine-regulated transcript peptide and the orexins are the latest discovered peptides acting at the level of the hypothalamus. Targets for new drugs acting on peptides secreted from the periphery are cholecystokinin and glucagon-like peptide 1. Another potential target in the treatment of obesity is increasing energy expenditure via β3 adrenoceptors or uncoupling proteins. These new pharmacological agents in development could be valuable adjuncts to more traditional treatment strategies such as dietary treatment, behavioural/psychological counselling and physical activity.

Kuczmarski RJ, Flegal KM, Campbell SM, et al. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys 1960 to 1991. JAMA 1994; 272: 205–11

World Health Organization. Obesity: preventing and managing the global epidemic: report of a WHO consultation on obesity 3–5 June: Geneva, 1997

Kolanowski J. Surgical treatment for morbid obesity. Br Med Bull 1997; 53: 433–44PubMedCrossRef

Zhang YY, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–32PubMedCrossRef

McNeely W, Benfield P. Orlistat. Drugs 1998; 56: 241–9PubMedCrossRef

McNeely W, Goa KL. Sibutramine: a review of its contribution to the management of obesity. Drugs 1998; 56: 1093–124PubMedCrossRef

Van Gaal LF, Wauters MA, Mertens IL, et al. Clinical endocrinology of human leptin. Int J Obes 1999; 23 Suppl. 1: 29–36CrossRef

Considine RV, Sinha MK, Heiman ML, et al. Serum immuno-reactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292–5PubMedCrossRef

Arch JRS, Stock MJ, Trayhurn P. Leptin resistance in obese humans: does it exist and what does it mean? Int J Obes 1998; 22: 1159–63CrossRef

10.

Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903–7PubMedCrossRef

11.

Strobel A, Issad T, Camoin L, et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18: 213–15PubMedCrossRef

12.

Clément K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401PubMedCrossRef

13.

Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879–84PubMedCrossRef

14.

Trayhurn P, Hoggard N, Mercer JG, et al. Leptin: fundamental aspects. Int J Obes 1999; 23 Suppl. 1: 22–8CrossRef

15.

Campfield LA, Smith FJ, Burn P. Strategies and potential molecular targets for obesity treatment. Science 1998; 280: 1383–7PubMedCrossRef

16.

Equivocal results for Amgen’s leptin? Scrip 1997; 2243: 24

17.

Woodworth JR, Howey DC, Bowsher RR et al. The pharmacokinetics and acute effects of LY355101, a novel antiobesity protein in healthy volunteers [abstract]. Int J Obes 1998; 22 Suppl. 3: S63

18.

Fink H, Rex A, Voits M, et al. Major biological actions of CCK: a critical evaluation of research findings. Exp Brain Res 1998; 123: 77–83PubMedCrossRef

19.

Lieverse RJ, Jansen JBMJ, Masclee AAM, et al. Satiety effects of cholecystokinin in humans. Gastroenterology 1994; 106: 1451–4PubMed

20.

Moran TH, Ameglio PJ, Peyton HJ, et al. Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys. Am J Physiol 1993; 265: R620–4PubMed

21.

Zarbin MA, Wamsley JK, Innis RB. Cholecystokinin receptors: presence on axonal flow in the rat vagus nerve. Life Sci 1981; 29: 697–705PubMedCrossRef

22.

Barrachina MD, Martinez V, Wang L, et al. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci U S A 1997; 94: 10455–60PubMedCrossRef

23.

Matson CA, Ritter RC. Long-term CCK-leptin synergy suggests a role for CCK in the regulation of body weight. Am J Physiol 1999; 45: 1038–45

24.

Emond M, Schwartz GJ, Ladenheim EE, et al. Central leptin modulates behavioural and neural responsivity to CCK. Am J Physiol 1999; 276: R1545–9PubMed

25.

Blundell JE, Haiford CG. Pharmacological aspects of obesity treatment: towards the 21st century. Int J Obes 1995; 19 Suppl. 3: S51–5

26.

Jack DB. Fighting obesity the Franco-British way. Lancet 1996; 347: 1756PubMedCrossRef

27.

Holst JJ. Glucagonlike peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology 1994; 107: 1848–55PubMed

28.

Creutzfeldt W. The incretin concept today. Diabetologia 1979; 16: 75–85PubMedCrossRef

29.

Holst JJ. Treatment of type 2 diabetes with glucagonlike peptide 1. Curr Opinion Endocrinol Diabetes 1998; 5: 108–15CrossRef

30.

Näslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide (GLP-1) in obese men. Int J Obes 1999; 23: 304–11CrossRef

31.

Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515–20PubMedCrossRef

32.

Näslund E, Gutniak M, Skogar S, et al. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr 1998; 68: 525–30PubMed

33.

Gutzwiller JP, Drewe J, Göke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999; 276: R1541–4PubMed

34.

Ranganath LR, Beety JM, Morgan LM, et al. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996; 38: 916–9PubMedCrossRef

35.

Flint A, Raben A, Rehfeld JF, et al. The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes 2000; 24: 288–98CrossRef

36.

Kanse SM, Kreymann B, Ghatei MA, et al. Identification and characterization of glucagon-like peptide-1 7-36 amide binding sites in the rat brain and lung. FEBS Lett 1988; 241: 209–12PubMedCrossRef

37.

Hassan M, Eskilsson A, Nilsson C, et al. In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7–36) amide in rat studied by gamma-camera. Nucl Med Biol 1999; 26: 413–20PubMedCrossRef

38.

Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 69–72PubMedCrossRef

39.

Scrocchi LA, Drucker DJ. Effects of ageing and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor-/-mice. Endocrinology 1998; 132: 3127–32CrossRef

40.

Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995; 80: 952–7PubMedCrossRef

41.

De Meester I, Korom S, Van Damme J, et al. CD 26, let it cut or cut it down. Immunol Today 1999; 20: 367–75PubMedCrossRef

42.

Burcelin R, Dolci W, Thorens B. Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analogue of glucagon-like peptide 1. Metabolism 1999; 48: 252–8PubMedCrossRef

43.

Pauly RP, Demuth HU, Rosche F. Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor in Ile-Thiazolidide. Metabolism 1999; 48: 385–9PubMedCrossRef

44.

Kolterman O, Fineman M, Gottlieb A, et al. AC2993 (synthetic exendin-4) lowered postprandial plasma glucose concentrations in people with type 2 diabetes [abstract]. The 39th Annual meeting of the European Association for the Study of Diabetes; 1999 Sep 28–Oct 2: Brussels

45.

Munglani R, Hudspith MJ, Hunt SP. The therapeutic potential of neuropeptide Y. Analgesic, anxiolytic and anithypertensive. Drugs 1996; 52: 371–89

46.

Clark JT, Kalra PS, Crowley WR, et al. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984; 115: 427–9PubMedCrossRef

47.

Wang J, Akabayashi A, Dourmashkin J, et al. Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity. Brain Res 1998; 802: 75–88PubMedCrossRef

48.

Billington CJ, Briggs JE, Harker S, et al. Neuropeptide Y in hypothalamic paraventricular nucleus: a centre co-ordinating energy metabolism. Am J Physiol 1994; 266: R1765–70PubMed

49.

Stephens TW, Basinski M, Bristow PK, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995; 377: 530–2PubMedCrossRef

50.

Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide. Y Nature 1996; 381: 415–8CrossRef

51.

Gerald C, Walker MW, Criscione L, et al. A receptor subtype involved in neuropeptide-Y induced food intake. Nature 1996; 11: 168–71CrossRef

52.

Inui A. Neuropeptide Yfeeding receptors: are multiple subtypes involved? Trends Pharm Sci 1999; 20: 43–6PubMedCrossRef

53.

Kanatani A, Ishihara A, Asahi S, et al. Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake. Endocrinology 1996; 137: 3177–82PubMedCrossRef

54.

Wieland HA, Engel W, Eberlein W, et al. Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect of feeding in rodents. Br J Pharmacol 1998; 125: 549–55PubMedCrossRef

55.

Criscione L, Rigollier P, Batzl-Hartmann C, et al. Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J Clin Invest 1998; 15: 2136–45CrossRef

56.

Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997; 138: 4489–92PubMedCrossRef

57.

Woods SC, Seeley RJ, Porte D, et al. Signals that regulate food intake and energy homeostasis. Science 1998; 280: 1378–83PubMedCrossRef

58.

Schioth HB, Muceniece R, Larsson M, et al. The melanocortin 1,3,4 or 5 receptors do not have binding epitope for ACTH beyond the sequence of alpha-MSH. J Endocrinol 1997; 155: 73PubMedCrossRef

59.

Fan W, Boston BA, Kesterson RA, et al. Role of melanocor-tinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 165–8PubMedCrossRef

60.

Fisher SL, Yagaloff KA, Burn P. Melanocortin-4 receptor: a novel signalling pathway involved in body weight regulation. Int J Obes 1999; 23 Suppl. 1: 54–8CrossRef

61.

Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–41PubMedCrossRef

62.

Ollmann MM, Wilson BD, Yang YK, et al. Antagonism of central melancortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 135–8PubMedCrossRef

63.

Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 1999; 140: 814–7PubMedCrossRef

64.

Qu D, Ludwig DS, Gammeltoft S, et al. Arole for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996; 380: 243–6PubMedCrossRef

65.

Shimada M, Tritos NA, Lowell BB, et al. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998; 396: 670–4PubMedCrossRef

66.

Chambers J, Ames RS, Bergsma D, et al. Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 1999; 400: 261–5PubMedCrossRef

67.

Douglass J, McKinzie AA, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci 1995; 15: 2471–81PubMed

68.

Lambert PD, Couceyro PR, McGirr KM, et al. CART peptides in the central role of feeding and interactions with neuropeptide. Y Synapse 1998; 29: 293–8CrossRef

69.

Kristensen P, Judge ME, Thim L, et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 1998; 393: 72–6PubMedCrossRef

70.

Kuhar MJ, Dall Vechia SE. CART peptides: novel addiction-and feeding related neuropeptides. Trends Neurosci 1999; 22: 316–20PubMedCrossRef

71.

Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573–85PubMedCrossRef

72.

De Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamic-specific peptide with neuroexicitatory activity. Proc Natl Acad Sci U S A 1998; 95: 322–7PubMedCrossRef

73.

Beck B, Richy S. Hypothalamic hypocretin/orexin and neuropeptide Y divergent interaction with energy depletion and leptin. Biochem Biophys Res Commun 1999; 258: 119–22PubMedCrossRef

74.

Trivedi P, Yu H, MacNeil DJ, et al. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438: 71–5PubMedCrossRef

75.

Lin L, Faraco J, Kadotani, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365–76PubMedCrossRef

76.

Tempel DL, Leibowitz KJ, Leibowitz SF. Effects of PVN galanin on macronutrient selection. Peptides 1988; 9: 309–14PubMedCrossRef

77.

Costa A, Poma A, Martignoni E, et al. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin from hypothalamic explants. Neuroreport 1997; 8: 1131–4PubMedCrossRef

78.

Arch JRS, Ainsworth AT. Thermogenic and antiobesity activity of a novel β-adrenoceptor agonist (BRL 26830A) in mice and rats. Am J Clin Nutr 1983; 38: 549–58PubMed

79.

Arch JRS. The brown adipocyte β-adrenoceptor. Proc Nutr Soc 1989; 48: 215–23PubMedCrossRef

80.

Clément K, Vaisse C, Manning BSJ, et al. Genetic variation in the β3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 1995; 333: 352–4PubMedCrossRef

81.

Widdén E, Lehto M, Kanninen T, et al. Association of a polymorphism in the β3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 1995; 333: 348–51CrossRef

82.

Walston J, Silver K, Bogardus C, et al. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic-receptor gene. N Engl J Med 1995; 333: 343–7PubMedCrossRef

83.

Buettner R, Schaffler A, Arndth H, et al. The TRP64ARG polymorphism of the beta 3-adrenergic receptor gene is not associated with obesity or type 2 diabetes mellitus in a large population-based Caucasian cohort. J Clin Endocrinol Metab 1998: 83: 2892–7PubMedCrossRef

84.

Allison DB, Heo M, Faith MS, et al. Meta-analysis of the association of the Trp64Arg polymorphism in the β3 adrenergic receptor with body mass index. Int J Obes 1998; 22: 559–66CrossRef

85.

Holloway BR, Howe R, Rao BS, et al. ICI D7114: a novel selective adrenoceptor agonist of brown fat and thermogenesis. Am J Clin Nutr 1992; 55: 262S–4SPubMed

86.

Fisher MH, Amend AM, Bach TJ, et al. A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. J Clin Invest 1998; 101: 2387–93PubMedCrossRef

87.

Arch JRS, Wilson S. Prospects for β3-adrenoceptor agonists in the treatment of obesity and diabetes. IntJObes 1996; 20: 191–9

88.

Weyer C, Gautier JF, Danforth E. Development of beta₃-adrenoceptor agonists for the treatment of obesity and diabetes —an update. Diabetes Metab 1999; 25: 11–21PubMed

89.

Connacher AA, Bennett WM, Jung RT. Clinical studies with the β3-adrenoceptor agonist BRL 26830A. Am J Clin Nutr 1992; 55 Suppl 252S–5S

90.

Weyer C, Tataranni PA, Snither S, et al. Increase in insulin action and fat oxidation after treatment with CL316,243 a highly selective beta3-adrenoceptor agonist in humans. Diabetes 1998; 47: 1555–610PubMedCrossRef

91.

Calles-Escandon J, Steiner K, Danforth E. Increased lipolysis in obese insulin resistant individuals after 3 months of treatment with a highly selective β3-adrenergic receptor (β3AR) agonist. Obes Res 1997; 5 Suppl. 1: 5S

92.

Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol Rev 1984; 64: 1–64PubMed

93.

Ricquier D, Fleury C, Larose M, et al. Contributions of studies on uncoupling proteins to research on metabolic diseases. J Int Med 1999; 245: 637–42CrossRef

94.

Clément K, Ruiz J, Cassard-Doulcier AM, et al. Additive effect of A t G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the β3-adrenergic receptor gene on weight gain in morbid obesity. Int J Obes 1996; 20: 1062–66

95.

Oppert JM, Vohl MC, Chagnon M, et al. DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. Int J Obes 1994; 18: 526–31

96.

Gagnon J, Lago F, Chagnon YC, et al. DNA polymorphism in the uncoupling protein 1 (UCP1) gene has no effect on obesity related phenotypes in the Swedish Obese Subjects cohorts. Int J Obes 1998; 22: 500–5CrossRef

97.

Luyckx FH, Scheen AJ, Proenza AM, et al. Influence of the A→G (-3826) uncoupling protein-1 gene (UCP1) variant on the dynamics of body weight before and after gastroplasty in morbidly obese subjects. Int J Obes 1998; 22: 1244–5CrossRef

98.

Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genetics 1997; 15: 269–70PubMedCrossRef

99.

Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein-3: a new member of the mitochondrial carrierfamily with tissue-specific distribution. FEBS Lett 1997; 408: 39–42PubMedCrossRef

100.

Gong DW, He Y, Karas M, et al. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β3-adrenergi agonists, and leptin. JBiol Chem 1997; 272: 24129–32CrossRef

101.

Bouchard C, Perusse L, Chagnon Y, et al. Linkage between markers in the vicinity of the uncoupling protein gene and resting metabolic rate in humans. Hum Mol Genet 1997; 6: 1887–9PubMedCrossRef

102.

Elbein SC, Leppert M, Hasstedt S. Uncoupling protein 2 region on chromosome 11q13 is not linked to markers of obesity in familial type 2 diabetes. Diabetes 1997; 46: 2105–7PubMed

103.

Schrauwen P, Xia J, Bogardus C, et al. Skeletal muscle UCP3 expression is a determinant of energy expenditure in Pima Indians. Diabetes 1999; 48: 146–9PubMedCrossRef

104.

Boss O, Muzzin P, Giacobino JP. The uncoupling proteins, a review. Eur J Endocrinol 1998; 139: 1–9PubMedCrossRef

Titel: Promising New Approaches to the Management of Obesity
verfasst von: Ilse L. Mertens
Dr Luc F. Van Gaal
Publikationsdatum: 01.07.2000
Verlag: Springer International Publishing
Erschienen in: Drugs / Ausgabe 1/2000
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI: https://doi.org/10.2165/00003495-200060010-00001

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Promising New Approaches to the Management of Obesity

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Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

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