The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists

Review

Abstract

Although β3-adrenoceptor (β3AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and receptor pharmacology. β3AR agonists, some of which also stimulate other βARs in humans, selectively stimulate fat oxidation in rodents and humans. This appears to be why they improve insulin sensitivity and reduce body fat whilst preserving lean body mass. Regulatory authorities ask that novel anti-obesity drugs improve insulin sensitivity and reduce mainly body fat. Drugs that act on different targets to stimulate fat oxidation may also offer these benefits. Stimulation of energy expenditure may be easy to detect only when the sympathetic nervous system is activated. Leptin resembles β3AR agonists in that it increases fat oxidation, energy expenditure and insulin sensitivity. This is partly because it raises sympathetic activity, but it may also promote fat oxidation by directly stimulating muscle leptin receptors. The β1AR and β2AR can, like the β3AR, display atypical pharmacologies. Moreover, the β3AR can display variable pharmacologies of its own, depending on the radioligand used in binding studies or the functional response measured. Studies on the β3AR demonstrate both the difficulties of predicting the in vivo effects of agonist drugs from in vitro data and that there may be opportunities for identifying drugs that act at a single receptor but have different profiles in vivo.

Keywords

β3-adrenoceptor agonist Atypical β-adrenoceptor Leptin Energy expenditure Fat oxidation Obesity drug Insulin sensitivity Ligand-directed signalling 

References

  1. Abraham R, Zed C, Mitchell T, Parr J, Wynn V (1987) The effect of a novel β-agonist BRL 26830A on weight and protein loss in obese patients. Int J Obes 11:306AGoogle Scholar
  2. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291:2613–2616PubMedGoogle Scholar
  3. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ (2003) Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci U S A 100:10207–10212PubMedGoogle Scholar
  4. Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingstrom G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, Fiedler M, Bergqvist E, Ohman B, Bjorkstrand E, Abrahmsen LB (2003) Selective inhibition of 11 β-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology 144:4755–4762PubMedGoogle Scholar
  5. Almond RE, Cawthorne MA, Enser M (1988) Muscles of diabetic (db/db) mice: fibre size, fibre type and the effects of a thermogenic, β-adrenoceptor agonist. Int J Obes 12:81–91PubMedGoogle Scholar
  6. Alonso LG, Maren TH (1955) Effect of food restriction on body composition of hereditary obese mice. Am J Physiol 183:284–290PubMedGoogle Scholar
  7. Arch JR (1981) The contribution of increased thermogenesis to the effect of anorectic drugs on body composition in mice. Am J Clin Nutr 34:2763–2769PubMedGoogle Scholar
  8. Arch JRS (2000) β3-adrenoreceptor ligands and the pharmacology of the β3-adrenoreceptor. In: Strosberg A (ed) The b3-adrenoreceptor. Taylor and Francis, London, pp 48–76Google Scholar
  9. Arch JR (2002) β3-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol 440:99–107PubMedGoogle Scholar
  10. Arch JRS (2007) Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 50:239–240Google Scholar
  11. Arch JR, Ainsworth AT (1983) Thermogenic and antiobesity activity of a novel β-adrenoceptor agonist (BRL 26830A) in mice and rats. Am J Clin Nutr 38:549–558PubMedGoogle Scholar
  12. Arch JRS, Kaumann AJ (1993) β3 and atypical β-adrenoceptors. Med Res Rev 13:663–729PubMedGoogle Scholar
  13. Arch JR, Ainsworth AT, Cawthorne MA (1982) Thermogenic and anorectic effects of ephedrine and congeners in mice and rats. Life Sci 30:1817–1826PubMedGoogle Scholar
  14. Arch JRS, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE, Wilson C, Wilson S (1984a) Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature 309:163–165PubMedGoogle Scholar
  15. Arch JRS, Ainsworth AT, Ellis RDM, Piercy V, Thody VE, Thurlby PL, Wilson C, Wilson S, Young P (1984b) Treatment of obesity with thermogenic β-adrenoceptor agonists: studies on BRL 26830A in rodents. Int J Obes 8(Suppl 1):1–11PubMedGoogle Scholar
  16. Arch JRS, Piercy V, Thurlby PL, Wilson C, Wilson S (1987) Thermogenic and lipolytic drugs for the treatment of obesity: old ideas and new possibilities. In: Berry EM, Blondheim SH, Eliahou HE, Shafrir E (eds) Recent advances in obesity research. John Libbey, London, pp 300–311Google Scholar
  17. Arch JRS, Bywater RJ, Coney KA, Ellis RDM, Thurlby PL, Smith SA, Zed C (1989) Influences on body composition and mechanism of action of the β-adrenoceptor agonist BRL 26830A. In: Lardy HA, Stratman F (eds) Proceedings of the Eighteenth Steenbeck Symposium, “Hormones, thermogenesis and obesity”. Elsevier, New York, pp 465–476Google Scholar
  18. Arch JRS, Cawthorne MA, Coney KA, Gusterson BA, Piercy V, Sennitt MV, Smith SA, Wallace J, Wilson S (1991) β-adrenoceptor-mediated control of thermogenesis, body composition and glucose homeostasis. In: Rothwell NJ, Stock MJ (eds) Obesity and Cachexia. Wiley, Chichester, pp 241–268Google Scholar
  19. Arch JR, Hislop D, Wang SJY, Speakman JR (2006) Some mathematical and technical issues in the measurement and interpretation of open-circuit indirect calorimetry in small animals. Int J Obes 30:1322–1331Google Scholar
  20. Asensio CD, Arsenijevic D, Lehr D, Giacobino J-P, Muzzin P, Rohner-Jeanrenaud F (2008) Effects of leptin on energy metabolism in β-less mice. Int J Obes (in press)Google Scholar
  21. Astrup A, Buemann B, Christensen NJ, Toubro S (1994) Failure to increase lipid oxidation in response to increasing dietary fat content in formerly obese women. Am J Physiol 266:E592–599PubMedGoogle Scholar
  22. Baker JG (2005a) Evidence for a secondary state of the human β3-adrenoceptor. Mol Pharmacol 68:1645–1655PubMedGoogle Scholar
  23. Baker JG (2005b) Site of action of β-ligands at the human β1-adrenoceptor. J Pharmacol Exp Ther 313:1163–1171PubMedGoogle Scholar
  24. Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 28:374–381PubMedGoogle Scholar
  25. Baker JG, Hall IP, Hill SJ (2003a) Agonist actions of “β-blockers” provide evidence for two agonist activation sites or conformations of the human β1-adrenoceptor. Mol Pharmacol 63:1312–1321PubMedGoogle Scholar
  26. Baker JG, Hall IP, Hill SJ (2003b) Agonist and inverse agonist actions of β-blockers at the human β2-adrenoceptor provide evidence for agonist-directed signaling. Mol Pharmacol 64:1357–1369PubMedGoogle Scholar
  27. Baker JG, Hall IP, Hill SJ (2003c) Influence of agonist efficacy and receptor phosphorylation on antagonist affinity measurements: differences between second messenger and reporter gene responses. Mol Pharmacol 64:679–688PubMedGoogle Scholar
  28. Barbe P, Millet L, Galitzky J, Lafontan M, Berlan M (1996) In situ assessment of the role of the β1-, β2- and β3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue. Br J Pharmacol 117:907–913PubMedGoogle Scholar
  29. Bardou M, Rouget C, Breuiller-Fouche M, Loustalot C, Naline E, Sagot P, Frydman R, Morcillo EJ, Advenier C, Leroy MJ, Morrison JJ (2007) Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs? BMC Pregnancy Childbirth 7(Suppl 1):S14PubMedGoogle Scholar
  30. Bebernitz GR, Schuster HF (2002) The impact of fatty acid oxidation on energy utilization: targets and therapy. Curr Pharm Des 8:1199–1227PubMedGoogle Scholar
  31. Biftu T, Feng DD, Liang GB, Kuo H, Qian X, Naylor EM, Colandrea VJ, Candelore MR, Cascieri MA, Colwell LF Jr., Forrest MJ, Hom GJ, MacIntyre DE, Stearns RA, Strader CD, Wyvratt MJ, Fisher MH, Weber AE (2000) Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective β3 adrenergic receptor agonist antiobesity agents. Bioorg Med Chem Lett 10:1431–1434PubMedGoogle Scholar
  32. Bitz C, Toubro S, Larsen TM, Harder H, Rennie KL, Jebb SA, Astrup A (2004) Increased 24-h energy expenditure in type 2 diabetes. Diabetes Care 27:2416–2421PubMedGoogle Scholar
  33. Blaak EE, Wolffenbuttel BH, Saris WH, Pelsers MM, Wagenmakers AJ (2001) Weight reduction and the impaired plasma-derived free fatty acid oxidation in type 2 diabetic subjects. J Clin Endocrinol Metab 86:1638–1644PubMedGoogle Scholar
  34. Breslow MJ, Min-Lee K, Brown DR, Chacko VP, Palmer D, Berkowitz DE (1999) Effect of leptin deficiency on metabolic rate in ob/ob mice. Am J Physiol 276:E443–449PubMedGoogle Scholar
  35. Buemann B, Sorensen TI, Pedersen O, Black E, Holst C, Toubro S, Echwald S, Holst JJ, Rasmussen C, Astrup A (2005) Lower-body fat mass as an independent marker of insulin sensitivity—the role of adiponectin. Int J Obes (Lond) 29:624–631Google Scholar
  36. Cavuoto P, McAinch AJ, Hatzinikolas G, Cameron-Smith D, Wittert GA (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69PubMedGoogle Scholar
  37. Chaston TB, Dixon JB, O’Brien PE (2007) Changes in fat-free mass during significant weight loss: a systematic review. Int J Obes (Lond) 31:743–750Google Scholar
  38. Chen HC, Farese RV Jr (2005) Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol 25:482–486PubMedGoogle Scholar
  39. Chen Y, Heiman ML (2000) Chronic leptin administration promotes lipid utilization until fat mass is greatly reduced and preserves lean mass of normal female rats. Regul Pept 92:113–119PubMedGoogle Scholar
  40. Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A, Distefano A, Hwang YJ, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI (2007a) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A 104:16480–16485PubMedGoogle Scholar
  41. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI (2007b) Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 282:22678–22688PubMedGoogle Scholar
  42. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713PubMedGoogle Scholar
  43. Clapham JC, Arch JR (2007) Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes Metab 9:259–275PubMedGoogle Scholar
  44. Cohen ML, Bloomquist W, Ito M, Lowell BB (2000) β3 receptors mediate relaxation in stomach fundus whereas a fourth β receptor mediates tachycardia in atria from transgenic β3 receptor knockout mice. Recept Channels 7:17–23PubMedGoogle Scholar
  45. Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS (1996) Role of leptin in fat regulation. Nature 380:677PubMedGoogle Scholar
  46. Connacher AA, Jung RT, Mitchell PE (1988) Weight loss in obese subjects on a restricted diet given BRL 26830A, a new atypical β-adrenoceptor agonist. Br Med J (Clin Res Ed) 296:1217–1220CrossRefGoogle Scholar
  47. Connacher AA, Bennet WM, Jung RT, Rennie MJ (1992) Metabolic effects of three weeks administration of the β-adrenoceptor agonist BRL 26830A. Int J Obes Relat Metab Disord 16:685–694PubMedGoogle Scholar
  48. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416PubMedGoogle Scholar
  49. Curioni C, Andre C (2006) Rimonabant for overweight or obesity. Cochrane Database Syst Rev:CD006162Google Scholar
  50. da Silva AA, Tallam LS, Liu J, Hall JE (2006) Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. Am J Physiol Regul Integr Comp Physiol 291:R1275–1282PubMedGoogle Scholar
  51. Darimont C, Turini M, Epitaux M, Zbinden I, Richelle M, Montell E, Ferrer-Martinez A, Mace K (2004) β3-adrenoceptor agonist prevents alterations of muscle diacylglycerol and adipose tissue phospholipids induced by a cafeteria diet. Nutr Metab (Lond) 1:4Google Scholar
  52. de Vente J, Bast A, Van Bree L, Zaagsma J (1980) β-Adrenoceptor studies. 6. Further investigations on the hybrid nature of the rat adipocyte β-adrenoceptor. Eur J Pharmacol 63:73–83PubMedGoogle Scholar
  53. Deng C, Paoloni-Giacobino A, Kuehne F, Boss O, Revelli J-P, Moinat M, Cawthorne MA, Muzzin P, Giacobino JP (1997) Respective degree of expression of β1-, β2- and β3-adrenoceptors in human brown and white adipose tissues. Br J Pharmacol 118:929–934Google Scholar
  54. Després JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134PubMedGoogle Scholar
  55. Dobbins RL, Szczepaniak LS, Zhang W, McGarry JD (2003) Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion. Am J Physiol Endocrinol Metab 284:E778–E787PubMedGoogle Scholar
  56. Dow RL (1997) β3-adrenergic agonists: potential therapeutics for obesity. Expert Opin Investig Drugs 6:1811–1825PubMedGoogle Scholar
  57. Dulloo AG, Miller DS (1984) Thermogenic drugs for the treatment of obesity: sympathetic stimulants in animal models. Br J Nutr 52:179–196PubMedGoogle Scholar
  58. Dulloo AG, Miller DS (1987) Screening of drugs for thermogenic anti-obesity properties: antidepressants. Ann Nutr Metab 31:69–80PubMedGoogle Scholar
  59. Dunbar JC, Hu Y, Lu H (1997) Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 46:2040–2043PubMedGoogle Scholar
  60. Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C, Strosberg AD (1989) Molecular characterization of the human β3-adrenergic receptor. Science 245:1118–1121PubMedGoogle Scholar
  61. Faria AN, Ribeiro Filho FF, Kohlmann NE, Gouvea Ferreira SR, Zanella MT (2005) Effects of sibutramine on abdominal fat mass, insulin resistance and blood pressure in obese hypertensive patients. Diabetes Obes Metab 7:246–253PubMedGoogle Scholar
  62. Farooqi IS, O’Rahilly S (2004) Monogenic human obesity syndromes. Recent Prog Horm Res 59:409–424PubMedGoogle Scholar
  63. Feng DD, Biftu T, Candelore MR, Cascieri MA, Colwell LF Jr, Deng L, Feeney WP, Forrest MJ, Hom GJ, MacIntyre DE, Miller RR, Stearns RA, Strader CD, Tota L, Wyvratt MJ, Fisher MH, Weber AE (2000) Discovery of an orally bioavailable alkyl oxadiazole β3 adrenergic receptor agonist. Bioorg Med Chem Lett 10:1427–1429PubMedGoogle Scholar
  64. Flatt JP (2007) Exaggerated claim about adaptive thermogenesis. Int J Obes (Lond) 31:1626 author reply 1627–1628Google Scholar
  65. Fujimoto WY, Jablonski KA, Bray GA, Kriska A, Barrett-Connor E, Haffner S, Hanson R, Hill JO, Hubbard V, Stamm E, Pi-Sunyer FX (2007) Body size and shape changes and the risk of diabetes in the diabetes prevention program. Diabetes 56:1680–1685PubMedGoogle Scholar
  66. Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muecholl E (eds) Catecholamines. Springer, New York, pp 283–335Google Scholar
  67. Furuta A, Thomas CA, Higaki M, Chancellor MB, Yoshimura N, Yamaguchi O (2006) The promise of β3-adrenoceptor agonists to treat the overactive bladder. Urol Clin North Am 33:539–543PubMedGoogle Scholar
  68. Galandrin S, Bouvier M (2006) Distinct signaling profiles of β1 and β2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol Pharmacol 70:1575–1584PubMedGoogle Scholar
  69. Galitzky J, Langin D, Verwaerde P, Montastruc JL, Lafontan M, Berlan M (1997) Lipolytic effects of conventional β3-adrenoceptor agonists and of CGP 12,177 in rat and human fat cells: preliminary pharmacological evidence for a putative β4-adrenoceptor. Br J Pharmacol 122:1244–1250PubMedGoogle Scholar
  70. Garrow JS, Webster J (1985) Are pre-obese people energy thrifty? Lancet 1:670–671PubMedGoogle Scholar
  71. Gavrilova O, Marcus-Samuels B, Reitman ML (2000) Lack of responses to a β3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice. Diabetes 49:1910–1916PubMedGoogle Scholar
  72. Gerhardt CC, Gros J, Strosberg AD, Issad T (1999) Stimulation of the extracellular signal-regulated kinase 1/2 pathway by human β-3 adrenergic receptor: new pharmacological profile and mechanism of activation. Mol Pharmacol 55:255–262PubMedGoogle Scholar
  73. Granneman JG, Lahners KN, Chaudhry A (1991) Molecular cloning and expression of the rat β3-adrenergic receptor. Mol Pharmacol 40:895–899PubMedGoogle Scholar
  74. Grasso P, Rozhavskaya-Arena M, Leinung MC, Lee DW (2001) [D-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice. Regul Pept 101:123–129PubMedGoogle Scholar
  75. Gros J, Manning BS, Pietri-Rouxel F, Guillaume JL, Drumare MF, Strosberg AD (1998) Site-directed mutagenesis of the human β3-adrenoceptor–transmembrane residues involved in ligand binding and signal transduction. Eur J Biochem 251:590–596PubMedGoogle Scholar
  76. Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB (1997) β3-adrenergic receptors on white and brown adipocytes mediate β3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 272:17686–17693PubMedGoogle Scholar
  77. Halaas JL, Boozer C, Blair West J, Fidahusein N, Denton DA, Friedman JM (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 94:8878–8883PubMedGoogle Scholar
  78. Harms HH (1976) Stereochemical aspects of β-adrenoceptor antagonist-receptor interaction in adipocytes. Differentiation of β-adrenoceptors in human and rat adipocytes. Life Sci 19:1447–1452PubMedGoogle Scholar
  79. Harms HH, Zaagsma J, Van der Wal B (1974) β-adrenoceptor studies. III. On the β-adrenoceptors in rat adipose tissue. Eur J Pharmacol 25:87–91PubMedGoogle Scholar
  80. Harms HH, Zaagsma J, de Vente J (1977) Differentiation of β-adrenoceptors in right atrium, diaphragm and adipose tissue of the rat, using stereoisomers of propranolol, alprenolol, nifenalol and practolol. Life Sci 21:123–128PubMedGoogle Scholar
  81. Harrington WW, Britt CS, Wilson JG, Milliken NO, Binz JG, Lobe DC, Oliver WR, Lewis MC, Ignar DM (2007) The effect of PPARα, PPARδ, PPARγ, and PPARpan agonists on body weight, body mass, and serum lipid profiles in diet-induced obese AKR/J mice. PPAR Res 2007:97125PubMedGoogle Scholar
  82. Harwood HJ Jr, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, Magee WP, Dalvie DK, Soliman VF, Martin WH, Mularski CJ, Eisenbeis SA (2003) Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem 278:37099–37111PubMedGoogle Scholar
  83. Hausberg M, Morgan DA, Mitchell JL, Sivitz WI, Mark AL, Haynes WG (2002) Leptin potentiates thermogenic sympathetic responses to hypothermia: a receptor-mediated effect. Diabetes 51:2434–2440PubMedGoogle Scholar
  84. Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, Nunes CN, Olson SH, Pikounis B, Ren N, Robertson N, Schaeffer JM, Shah K, Springer MS, Strack AM, Strowski M, Wu K, Wu T, Xiao J, Zhang BB, Wright SD, Thieringer R (2005) 11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 202:517–527PubMedGoogle Scholar
  85. Heubach JF, Ravens U, Kaumann AJ (2004) Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human β2-adrenoceptors overexpressed in mouse heart. Mol Pharmacol 65:1313–1322PubMedGoogle Scholar
  86. 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, A randomized, controlled, dose-escalation trial. JAMA 282:1568–1575PubMedGoogle Scholar
  87. Hidaka S, Yoshimatsu H, Kondou S, Tsuruta Y, Oka K, Noguchi H, Okamoto K, Sakino H, Teshima Y, Okeda T, Sakata T (2002) Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J 16:509–518PubMedGoogle Scholar
  88. Hirsch J, Mackintosh RM, Aronne LJ (2000) The effects of drugs used to treat obesity on the autonomic nervous system. Obes Res 8:227–233PubMedGoogle Scholar
  89. Hoeks J, van Baak MA, Hesselink MK, Hul GB, Vidal H, Saris WH, Schrauwen P (2003) Effect of β1- and β2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans. Am J Physiol Endocrinol Metab 285:E775–782PubMedGoogle Scholar
  90. Holloway BR (1989) Reactivation of brown adipose tissue. Proc Nutr Soc 48:225–230PubMedGoogle Scholar
  91. Hutchinson DS, Sato M, Evans BA, Christopoulos A, Summers RJ (2005) Evidence for pleiotropic signaling at the mouse β3-adrenoceptor revealed by SR59230A [3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propa nol oxalate]. J Pharmacol Exp Ther 312:1064–1074PubMedGoogle Scholar
  92. Hutchinson DS, Chernogubova E, Sato M, Summers RJ, Bengtsson T (2006) Agonist effects of zinterol at the mouse and human β(3)-adrenoceptor. Naunyn Schmiedebergs Arch Pharmacol 373:158–168PubMedGoogle Scholar
  93. Hwa JJ, Ghibaudi L, Compton D, Fawzi AB, Strader CD (1996) Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice. Horm Metab Res 28:659–663PubMedGoogle Scholar
  94. Hwa JJ, Fawzi AB, Graziano MP, Ghibaudi L, Williams P, Van Heek M, Davis H, Rudinski M, Sybertz E, Strader CD (1997) Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice. Am J Physiol 272:R1204–R1209PubMedGoogle Scholar
  95. Ida K, Hashimoto K, Kamiya M, Muto S, Nakamura Y, Kato K, Mizota M (1996) Stereoselective action of (R*,R*)-(+/−)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino] propyl]-phenoxyacetic acid (BRL37344) on β-adrenoceptors and metabolic chiral inversion. Biochem Pharmacol 52:1521–1527PubMedGoogle Scholar
  96. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 356:2119–2125PubMedGoogle Scholar
  97. Jensen MD (2006) Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model. Obesity (Silver Spring) 14(Suppl 1):20S–24SGoogle Scholar
  98. Jeon JY, Steadward RD, Wheeler GD, Bell G, McCargar L, Harber V (2003) Intact sympathetic nervous system is required for leptin effects on resting metabolic rate in people with spinal cord injury. J Clin Endocrinol Metab 88:402–407PubMedGoogle Scholar
  99. Joseph SS, Colledge WH, Kaumann AJ (2004a) Aspartate138 is required for the high-affinity ligand binding site but not for the low-affinity binding site of the β1-adrenoceptor. Naunyn Schmiedebergs Arch Pharmacol 370:223–226PubMedGoogle Scholar
  100. Joseph SS, Lynham JA, Colledge WH, Kaumann AJ (2004b) Binding of (−)-[3H]-CGP12177 at two sites in recombinant human β1-adrenoceptors and interaction with β-blockers. Naunyn Schmiedebergs Arch Pharmacol 369:525–532PubMedGoogle Scholar
  101. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451PubMedGoogle Scholar
  102. Kaumann AJ (1989) Is there a third heart β-adrenoceptor? Trends Pharmacol Sci 10:316–320PubMedGoogle Scholar
  103. Kaumann AJ (1997) Four β-adrenoceptor subtypes in the mammalian heart. Trends Pharmacol Sci 18:70–76PubMedGoogle Scholar
  104. Kaumann AJ, Molenaar P (1996) Differences between the third cardiac β-adrenoceptor and the colonic β3-adrenoceptor in the rat. Br J Pharmacol 118:2085–2098PubMedGoogle Scholar
  105. Kaumann AJ, Preitner F, Sarsero D, Molenaar P, Revelli JP, Giacobino JP (1998) (−)-CGP 12177 causes cardiostimulation and binds to cardiac putative β4-adrenoceptors in both wild-type and β3-adrenoceptor knockout mice. Mol Pharmacol 53:670–675PubMedGoogle Scholar
  106. Kaumann AJ, Engelhardt S, Hein L, Molenaar P, Lohse M (2001) Abolition of (−)-CGP 12177-evoked cardiostimulation in double β12-adrenoceptor knockout mice. Obligatory role of β1-adrenoceptors for putative β4-adrenoceptor pharmacology. Naunyn Schmiedebergs Arch Pharmacol 363:87–93PubMedGoogle Scholar
  107. Kaumann A, Semmler AB, Molenaar P (2007) The effects of both noradrenaline and CGP12177, mediated through human β1-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 375:123–131PubMedGoogle Scholar
  108. Kawashita NH, Moura MA, Brito MN, Brito SM, Garofalo MA, Kettelhut IC, Migliorini RH (2002) Relative importance of sympathetic outflow and insulin in the reactivation of brown adipose tissue lipogenesis in rats adapted to a high-protein diet. Metabolism 51:343–349PubMedGoogle Scholar
  109. Kelley DE, Kuller LH, McKolanis TM, Harper P, Mancino J, Kalhan S (2004) Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabetes Care 27:33–40PubMedGoogle Scholar
  110. Kim-Motoyama H, Yasuda K, Yamaguchi T, Yamada N, Katakura T, Shuldiner AR, Akanuma Y, Ohashi Y, Yazaki Y, Kadowaki T (1997) A mutation of the β3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride. Diabetologia 40:469–472PubMedGoogle Scholar
  111. Konkar AA, Zhai Y, Granneman JG (2000) β1-adrenergic receptors mediate β3-adrenergic-independent effects of CGP 12177 in brown adipose tissue. Mol Pharmacol 57:252–258PubMedGoogle Scholar
  112. Kurokawa N, Nakai K, Kameo S, Liu ZM, Satoh H (2001) Association of BMI with the β3-adrenergic receptor gene polymorphism in Japanese: meta-analysis. Obes Res 9:741–745PubMedGoogle Scholar
  113. Lafontan M, Piazza PV, Girard J (2007) Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients. Diabetes Metab 33:85–95PubMedGoogle Scholar
  114. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A (2002) Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr 76:780–788PubMedGoogle Scholar
  115. Larson DE, Ferraro RT, Robertson DS, Ravussin E (1995) Energy metabolism in weight-stable postobese individuals. Am J Clin Nutr 62:735–739PubMedGoogle Scholar
  116. Leineweber K, Buscher R, Bruck H, Brodde OE (2004) β-adrenoceptor polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369:1–22PubMedGoogle Scholar
  117. Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F (1996) Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A 93:1726–1730PubMedGoogle Scholar
  118. 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 142:532–546PubMedGoogle Scholar
  119. Lin CY, Higginbotham DA, Judd RL, White BD (2002) Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 282:E1084–1091PubMedGoogle Scholar
  120. Livingston EH (2006) Lower body subcutaneous fat accumulation and diabetes mellitus risk. Surg Obes Relat Dis 2:362–368PubMedGoogle Scholar
  121. Malinowska B, Schlicker E (1996) Mediation of the positive chronotropic effect of CGP 12177 and cyanopindolol in the pithed rat by atypical β-adrenoceptors, different from β3-adrenoceptors. Br J Pharmacol 117:943–949PubMedGoogle Scholar
  122. Malinowska B, Schlicker E (1997) Further evidence for differences between cardiac atypical β-adrenoceptors and brown adipose tissue β3-adrenoceptors in the pithed rat. Br J Pharmacol 122:1307–1314PubMedGoogle Scholar
  123. Manara L, Croci T, Landi M (1995) β3-adrenoceptors and intestinal motility. Fundam Clin Pharmacol 9:332–342PubMedGoogle Scholar
  124. Massoudi M, Miller DS (1977) Ephedrine, a thermogenic and potential slimming drug. Proc Nutr Soc 36:135APubMedGoogle Scholar
  125. Massoudi M, Evans E, Miller DS (1983) Thermogenic drugs for the treatment of obesity: screening using obese rats and mice. Ann Nutr Metab 27:26–37PubMedGoogle Scholar
  126. Matsuda D, Tomoda H (2007) DGAT inhibitors for obesity. Curr Opin Investig Drugs 8:836–841PubMedGoogle Scholar
  127. Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119PubMedGoogle Scholar
  128. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343PubMedGoogle Scholar
  129. Mirshamsi S, Olsson M, Arnelo U, Kinsella JM, Permert J, Ashford ML (2007) BVT.3531 reduces body weight and activates K(ATP) channels in isolated arcuate neurons in rats. Regul Pept 141:19–24PubMedGoogle Scholar
  130. Mistry AM, Swick AG, Romsos DR (1997) Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 127:2065–2072PubMedGoogle Scholar
  131. Mitchell TH, Ellis RD, Smith SA, Robb G, Cawthorne MA (1989) Effects of BRL 35135, a β-adrenoceptor agonist with novel selectivity, on glucose tolerance and insulin sensitivity in obese subjects. Int J Obes 13:757–766PubMedGoogle Scholar
  132. Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9–S15PubMedGoogle Scholar
  133. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR (2004) Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 β-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 53:931–938PubMedGoogle Scholar
  134. Muzzin P, Revelli JP, Kuhne F, Gocayne JD, McCombie WR, Venter JC, Giacobino JP, Fraser CM (1991) An adipose tissue-specific β-adrenergic receptor. Molecular cloning and down-regulation in obesity. J Biol Chem 266:24053–24058PubMedGoogle Scholar
  135. Muzzin P, Boss O, Mathis N, Revelli JP, Giacobino JP, Willcocks K, Badman GT, Cantello BC, Hindley RM, Cawthorne MA (1994) Characterization of a new, highly specific, β3-adrenergic receptor radioligand, [3H]SB 206606. Mol Pharmacol 46:357–363PubMedGoogle Scholar
  136. Nahmias C, Blin N, Elalouf J-M, Mattei MG, Strosberg AD, Emorine LJ (1991) Molecular characterization of the mouse β3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J 10:3721–3727PubMedGoogle Scholar
  137. Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444–E452PubMedGoogle Scholar
  138. Nelson KM, Weinsier RL, Long CL, Schutz Y (1992) Prediction of resting energy expenditure from fat-free mass and fat mass. Am J Clin Nutr 56:848–856PubMedGoogle Scholar
  139. Niclauss N, Michel-Reher MB, Alewijnse AE, Michel MC (2006) Comparison of three radioligands for the labelling of human β-adrenoceptor subtypes. Naunyn Schmiedebergs Arch Pharmacol 374:99–105PubMedGoogle Scholar
  140. Oh W, Abu-Elheiga L, Kordari P, Gu Z, Shaikenov T, Chirala SS, Wakil SJ (2005) Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice. Proc Natl Acad Sci U S A 102:1384–1389PubMedGoogle Scholar
  141. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effects of the obese gene product on body weight in ob/ob mice. Science 269:540–543PubMedGoogle Scholar
  142. Rafael J, Herling AW (2000) Leptin effect in ob/ob mice under thermoneutral conditions depends not necessarily on central satiation. Am J Physiol Regul Integr Comp Physiol 278:R790–795PubMedGoogle Scholar
  143. Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C (1986) Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest 78:1568–1578PubMedGoogle Scholar
  144. Redman LM, Heilbronn LK, Martin CK, Alfonso A, Smith SR, Ravussin E (2007) Effect of calorie restriction with or without exercise on body composition and fat distribution. J Clin Endocrinol Metab 92:865–872PubMedGoogle Scholar
  145. Ritchie SA, Connell JM (2007) The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis 17:319–326PubMedGoogle Scholar
  146. Rouru J, Cusin I, Zakrzewska KE, Jeanrenaud B, Rohner-Jeanrenaud F (1999) Effects of intravenously infused leptin on insulin sensitivity and on the expression of uncoupling proteins in brown adipose tissue. Endocrinology 140:3688–3692PubMedGoogle Scholar
  147. Rucker D, Padwal R, Li SK, Curioni C, Lau DC (2007) Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335:1194–1199PubMedGoogle Scholar
  148. Ruige JB, Mertens I, Considine RV, Paelinck BP, Van Gaal LF (2006) Opposite effects of insulin-like molecules and leptin in coronary heart disease of type 2 diabetes Preliminary data. Int J Cardiol 111:19–25PubMedGoogle Scholar
  149. Sato M, Horinouchi T, Hutchinson DS, Evans BA, Summers RJ (2007) Ligand-directed signaling at the β3-adrenoceptor produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propan ol oxalate (SR59230A) relative to receptor agonists. Mol Pharmacol 72:1359–1368PubMedGoogle Scholar
  150. Scheidegger K, O’Connell M, Robbins DC, Danforth E Jr (1984) Effects of chronic β-receptor stimulation on sympathetic nervous system activity, energy expenditure, and thyroid hormones. J Clin Endocrinol Metab 58:895–903PubMedGoogle Scholar
  151. Schiffelers SL, Brouwer EM, Saris WH, van Baak MA (1998) Inhibition of lipolysis reduces β1-adrenoceptor-mediated thermogenesis in man. Metabolism 47:1462–1467PubMedGoogle Scholar
  152. Schiffelers SL, van Harmelen VJ, de Grauw HA, Saris WH, van Baak MA (1999) Dobutamine as selective β1-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization. J Appl Physiol 87:977–981PubMedGoogle Scholar
  153. Schiffelers SL, Blaak EE, Saris WH, van Baak MA (2000) In vivo β3-adrenergic stimulation of human thermogenesis and lipid use. Clin Pharmacol Ther 67:558–566PubMedGoogle Scholar
  154. Schiffelers SL, Saris WH, Boomsma F, van Baak MA (2001a) β1- and β2-Adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men. J Clin Endocrinol Metab 86:2191–2199PubMedGoogle Scholar
  155. Schiffelers SL, Saris WH, van Baak MA (2001b) The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men. Int J Obes Relat Metab Disord 25:33–38PubMedGoogle Scholar
  156. Schmidt MI, Duncan BB, Vigo A, Pankow JS, Couper D, Ballantyne CM, Hoogeveen RC, Heiss G (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 49:2086–2096PubMedGoogle Scholar
  157. Schmitz-Peiffer C, Craig DL, Biden TJ (1999) Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 274:24202–24210PubMedGoogle Scholar
  158. Seifert R, Gether U, Wenzel-Seifert K, Kobilka BK (1999) Effects of guanine, inosine, and xanthine nucleotides on β(2)-adrenergic receptor/G(s) interactions: evidence for multiple receptor conformations. Mol Pharmacol 56:348–358PubMedGoogle Scholar
  159. Sennitt MV, Kaumann AJ, Molenaar P, Beeley LJ, Young PW, Kelly J, Chapman H, Henson SM, Berge JM, Dean DK, Kotecha NR, Morgan HK, Rami HK, Ward RW, Thompson M, Wilson S, Smith SA, Cawthorne MA, Stock MJ, Arch JR (1998) The contribution of classical (β1/2-) and atypical β-adrenoceptors to the stimulation of human white adipocyte lipolysis and right atrial appendage contraction by novel β3-adrenoceptor agonists of differing selectivities. J Pharmacol Exp Ther 285:1084–1095PubMedGoogle Scholar
  160. Shi ZQ, Nelson A, Whitcomb L, Wang J, Cohen AM (1998) Intracerebroventricular administration of leptin markedly enhances insulin sensitivity and systemic glucose utilization in conscious rats. Metabolism 47:1274–1280PubMedGoogle Scholar
  161. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76PubMedGoogle Scholar
  162. Sivitz WI, Walsh SA, Morgan DA, Thomas MJ, Haynes WG (1997) Effects of leptin on insulin sensitivity in normal rats. Endocrinology 138:3395–3401PubMedGoogle Scholar
  163. Smith SA, Sennitt MV, Cawthorne MA (1990) BRL 35135: an orally active antihyperglycaemic agent with weight reducing effects. In: Bailey CJ, Flatt PR (eds) New antidiabetic drugs. Smith-Gordon, London, pp 177–189Google Scholar
  164. Solinas G, Summermatter S, Mainieri D, Gubler M, Pirola L, Wymann MP, Rusconi S, Montani JP, Seydoux J, Dulloo AG (2004) The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation. FEBS Lett 577:539–544PubMedGoogle Scholar
  165. Steinberg GR, Bonen A, Dyck DJ (2002) Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats. Am J Physiol Endocrinol Metab 282:E593–E600PubMedGoogle Scholar
  166. Stemmelin J, Cohen C, Terranova JP, Lopez-Grancha M, Pichat P, Bergis O, Decobert M, Santucci V, Francon D, Alonso R, Stahl SM, Keane P, Avenet P, Scatton B, le Fur G, Griebel G (2008) Stimulation of the β(3)-adrenoceptor as a novel treatment strategy for anxiety and depressive disorders. Neuropsychopharmacology 33:574–587PubMedGoogle Scholar
  167. Stiegler P, Cunliffe A (2006) The role of diet and exercise for the maintenance of fat-free mass and resting metabolic rate during weight loss. Sports Med 36:239–262PubMedGoogle Scholar
  168. Surmely JF, Voirol MJ, Stefanoni N, Assimacopoulos-Jeannet F, Giacobino JP, Jequier E, Gaillard RC, Tappy L (1998) Stimulation by leptin of 3H GDP binding to brown adipose tissue of fasted but not fed rats. Int J Obes Relat Metab Disord 22:923–926PubMedGoogle Scholar
  169. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (2007) Effect of (R)-2-(2-aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647PubMedGoogle Scholar
  170. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J (2003) Activation of peroxisome proliferator-activated receptor delta induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A 100:15924–15929PubMedGoogle Scholar
  171. Tchernof A, Starling RD, Turner A, Shuldiner AR, Walston JD, Silver K, Poehlman ET (2000) Impaired capacity to lose visceral adipose tissue during weight reduction in obese postmenopausal women with the Trp64Arg β3-adrenoceptor gene variant. Diabetes 49:1709–1713PubMedGoogle Scholar
  172. Thomas EL, Brynes AE, McCarthy J, Goldstone AP, Hajnal JV, Saeed N, Frost G, Bell JD (2000) Preferential loss of visceral fat following aerobic exercise, measured by magnetic resonance imaging. Lipids 35:769–776PubMedGoogle Scholar
  173. Thurlby PL, Trayhurn P (1979) The role of thermoregulatory thermogenesis in the development of obesity in genetically-obese (ob/ob) mice pair-fed with lean siblings. Br J Nutr 42:377–385PubMedGoogle Scholar
  174. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13PubMedGoogle Scholar
  175. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH (2002) Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 71:272–279PubMedGoogle Scholar
  176. Van Gaal LF, Wauters MA, Peiffer FW, De Leeuw IH (1998) Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? Int J Obes Relat Metab Disord 22(Suppl 1):S38–S40 discussion S41–32PubMedGoogle Scholar
  177. Vrydag W, Michel MC (2007) Tools to study β3-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 374:385–398PubMedGoogle Scholar
  178. Wang M (2006) Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 for the treatment of metabolic syndrome. Curr Opin Investig Drugs 7:319–323PubMedGoogle Scholar
  179. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM (2003) Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113:159–170PubMedGoogle Scholar
  180. Wang SJ, Birtles S, de Schoolmeester J, Swales J, Moody G, Hislop D, O’Dowd J, Smith DM, Turnbull AV, Arch JR (2006) Inhibition of 11β-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice. Diabetologia 49:1333–1337PubMedGoogle Scholar
  181. Wang SJ, Cornick C, O’Dowd J, Cawthorne MA, Arch JR (2007) Improved glucose tolerance in acyl CoA:diacylglycerol acyltransferase 1-null mice is dependent on diet. Lipids Health Dis 6:2PubMedGoogle Scholar
  182. Weyer C, Tataranni PA, Snitker S, Danforth E Jr, Ravussin E (1998) Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 47:1555–1561PubMedGoogle Scholar
  183. Wheeldon NM, McDevitt DG, Lipworth BJ (1993) Do β3-adrenoceptors mediate metabolic responses to isoprenaline. Q J Med 86:595–600PubMedGoogle Scholar
  184. Widdowson PS, Upton R, Pickavance L, Buckingham R, Tadayyon M, Arch J, Williams G (1998) Acute hyperleptinemia does not modify insulin sensitivity in vivo in the rat. Horm Metab Res 30:259–262PubMedCrossRefGoogle Scholar
  185. Wilson C, Wilson S, Piercy V, Sennitt MV, Arch JRS (1984a) The rat lipolytic β-adrenoceptor: studies using novel β-adrenoceptor agonists. Eur J Pharmacol 100:309–319PubMedGoogle Scholar
  186. Wilson S, Arch JRS, Thurlby PL (1984b) Genetically obese C57BL/6 ob/ob mice respond normally to sympathomimetic compounds. Life Sci 35:1301–1309PubMedGoogle Scholar
  187. Wilson S, Thurlby PL, Arch JR (1986) Substrate supply for thermogenesis induced by the β-adrenoceptor agonist BRL 26830A. Can J Physiol Pharmacol 65:113–119Google Scholar
  188. Wilson S, Chambers JK, Park JE, Ladurner A, Cronk DW, Chapman CG, Kallender H, Browne MJ, Murphy GJ, Young PW (1996) Agonist potency at the cloned human beta-3 adrenoceptor depends on receptor expression level and nature of assay. J Pharmacol Exp Ther 279:214–221PubMedGoogle Scholar
  189. Wing RR, Phelan S (2005) Long-term weight loss maintenance. Am J Clin Nutr 82:222S–225SPubMedGoogle Scholar
  190. Yaspelkis BB 3rd, Ansari L, Ramey EL, Holland GJ, Loy SF (1999) Chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport. Metabolism 48:671–676PubMedGoogle Scholar
  191. Yen TT, McKee MM, Bemis KG (1981) Ephedrine reduces weight of viable yellow obese mice (Avy/a). Life Sci 28:119–128PubMedGoogle Scholar
  192. Yu YH, Ginsberg HN (2004) The role of acyl-CoA:diacylglycerol acyltransferase (DGAT) in energy metabolism. Ann Med 36:252–261PubMedGoogle Scholar
  193. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI (2002) Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236PubMedGoogle Scholar
  194. Zhan S, Ho SC (2005) Meta-analysis of the association of the Trp64Arg polymorphism in the β3 adrenergic receptor with insulin resistance. Obes Res 13:1709–1719PubMedGoogle Scholar
  195. Zhao G, Souers AJ, Voorbach M, Falls HD, Droz B, Brodjian S, Lau YY, Iyengar RR, Gao J, Judd AS, Wagaw SH, Ravn MM, Engstrom KM, Lynch JK, Mulhern MM, Freeman J, Dayton BD, Wang X, Grihalde N, Fry D, Beno DW, Marsh KC, Su Z, Diaz GJ, Collins CA, Sham H, Reilly RM, Brune ME, Kym PR (2008) Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J Med Chem 51(3):380–383PubMedGoogle Scholar
  196. Zurlo F, Lillioja S, Esposito-Del Puente A, Nyomba BL, Raz I, Saad MF, Swinburn BA, Knowler WC, Bogardus C, Ravussin E (1990) Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol 259:E650–E657PubMedGoogle Scholar

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© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Clore LaboratoryUniversity of BuckinghamBuckinghamUK

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