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.
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References
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 11:306A
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 291:2613–2616
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 100:10207–10212
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 144:4755–4762
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 12:81–91
Alonso LG, Maren TH (1955) Effect of food restriction on body composition of hereditary obese mice. Am J Physiol 183:284–290
Arch JR (1981) The contribution of increased thermogenesis to the effect of anorectic drugs on body composition in mice. Am J Clin Nutr 34:2763–2769
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 48–76
Arch JR (2002) β3-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol 440:99–107
Arch JRS (2007) Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 50:239–240
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 38:549–558
Arch JRS, Kaumann AJ (1993) β3 and atypical β-adrenoceptors. Med Res Rev 13:663–729
Arch JR, Ainsworth AT, Cawthorne MA (1982) Thermogenic and anorectic effects of ephedrine and congeners in mice and rats. Life Sci 30:1817–1826
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 309:163–165
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):1–11
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 300–311
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 465–476
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 241–268
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 30:1322–1331
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)
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:E592–599
Baker JG (2005a) Evidence for a secondary state of the human β3-adrenoceptor. Mol Pharmacol 68:1645–1655
Baker JG (2005b) Site of action of β-ligands at the human β1-adrenoceptor. J Pharmacol Exp Ther 313:1163–1171
Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 28:374–381
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 63:1312–1321
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 64:1357–1369
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 64:679–688
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 117:907–913
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):S14
Bebernitz GR, Schuster HF (2002) The impact of fatty acid oxidation on energy utilization: targets and therapy. Curr Pharm Des 8:1199–1227
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 10:1431–1434
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 27:2416–2421
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 86:1638–1644
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:E443–449
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) 29:624–631
Cavuoto P, McAinch AJ, Hatzinikolas G, Cameron-Smith D, Wittert GA (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69
Chaston TB, Dixon JB, O’Brien PE (2007) Changes in fat-free mass during significant weight loss: a systematic review. Int J Obes (Lond) 31:743–750
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 25:482–486
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 92:113–119
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 104:16480–16485
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 282:22678–22688
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 370:1706–1713
Clapham JC, Arch JR (2007) Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes Metab 9:259–275
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 7:17–23
Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS (1996) Role of leptin in fat regulation. Nature 380:677
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) 296:1217–1220
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 16:685–694
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 3:403–416
Curioni C, Andre C (2006) Rimonabant for overweight or obesity. Cochrane Database Syst Rev:CD006162
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:R1275–1282
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) 1:4
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 63:73–83
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 118:929–934
Després JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134
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–E787
Dow RL (1997) β3-adrenergic agonists: potential therapeutics for obesity. Expert Opin Investig Drugs 6:1811–1825
Dulloo AG, Miller DS (1984) Thermogenic drugs for the treatment of obesity: sympathetic stimulants in animal models. Br J Nutr 52:179–196
Dulloo AG, Miller DS (1987) Screening of drugs for thermogenic anti-obesity properties: antidepressants. Ann Nutr Metab 31:69–80
Dunbar JC, Hu Y, Lu H (1997) Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 46:2040–2043
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 245:1118–1121
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 7:246–253
Farooqi IS, O’Rahilly S (2004) Monogenic human obesity syndromes. Recent Prog Horm Res 59:409–424
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 10:1427–1429
Flatt JP (2007) Exaggerated claim about adaptive thermogenesis. Int J Obes (Lond) 31:1626 author reply 1627–1628
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 56:1680–1685
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 283–335
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 33:539–543
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 70:1575–1584
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 122:1244–1250
Garrow JS, Webster J (1985) Are pre-obese people energy thrifty? Lancet 1:670–671
Gavrilova O, Marcus-Samuels B, Reitman ML (2000) Lack of responses to a β3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice. Diabetes 49:1910–1916
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 55:255–262
Granneman JG, Lahners KN, Chaudhry A (1991) Molecular cloning and expression of the rat β3-adrenergic receptor. Mol Pharmacol 40:895–899
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 101:123–129
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 251:590–596
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 272:17686–17693
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 94:8878–8883
Harms HH (1976) Stereochemical aspects of β-adrenoceptor antagonist-receptor interaction in adipocytes. Differentiation of β-adrenoceptors in human and rat adipocytes. Life Sci 19:1447–1452
Harms HH, Zaagsma J, Van der Wal B (1974) β-adrenoceptor studies. III. On the β-adrenoceptors in rat adipose tissue. Eur J Pharmacol 25:87–91
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 21:123–128
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 2007:97125
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 278:37099–37111
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 51:2434–2440
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 202:517–527
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 65:1313–1322
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 282:1568–1575
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 16:509–518
Hirsch J, Mackintosh RM, Aronne LJ (2000) The effects of drugs used to treat obesity on the autonomic nervous system. Obes Res 8:227–233
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:E775–782
Holloway BR (1989) Reactivation of brown adipose tissue. Proc Nutr Soc 48:225–230
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 312:1064–1074
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 373:158–168
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 28:659–663
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–R1209
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 52:1521–1527
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 356:2119–2125
Jensen MD (2006) Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model. Obesity (Silver Spring) 14(Suppl 1):20S–24S
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 88:402–407
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 370:223–226
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 369:525–532
Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451
Kaumann AJ (1989) Is there a third heart β-adrenoceptor? Trends Pharmacol Sci 10:316–320
Kaumann AJ (1997) Four β-adrenoceptor subtypes in the mammalian heart. Trends Pharmacol Sci 18:70–76
Kaumann AJ, Molenaar P (1996) Differences between the third cardiac β-adrenoceptor and the colonic β3-adrenoceptor in the rat. Br J Pharmacol 118:2085–2098
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 53:670–675
Kaumann AJ, Engelhardt S, Hein L, Molenaar P, Lohse M (2001) Abolition of (−)-CGP 12177-evoked cardiostimulation in double β1/β2-adrenoceptor knockout mice. Obligatory role of β1-adrenoceptors for putative β4-adrenoceptor pharmacology. Naunyn Schmiedebergs Arch Pharmacol 363:87–93
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 375:123–131
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 51:343–349
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 27:33–40
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 40:469–472
Konkar AA, Zhai Y, Granneman JG (2000) β1-adrenergic receptors mediate β3-adrenergic-independent effects of CGP 12177 in brown adipose tissue. Mol Pharmacol 57:252–258
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 9:741–745
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 33:85–95
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 76:780–788
Larson DE, Ferraro RT, Robertson DS, Ravussin E (1995) Energy metabolism in weight-stable postobese individuals. Am J Clin Nutr 62:735–739
Leineweber K, Buscher R, Bruck H, Brodde OE (2004) β-adrenoceptor polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369:1–22
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 93:1726–1730
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
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:E1084–1091
Livingston EH (2006) Lower body subcutaneous fat accumulation and diabetes mellitus risk. Surg Obes Relat Dis 2:362–368
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 117:943–949
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 122:1307–1314
Manara L, Croci T, Landi M (1995) β3-adrenoceptors and intestinal motility. Fundam Clin Pharmacol 9:332–342
Massoudi M, Miller DS (1977) Ephedrine, a thermogenic and potential slimming drug. Proc Nutr Soc 36:135A
Massoudi M, Evans E, Miller DS (1983) Thermogenic drugs for the treatment of obesity: screening using obese rats and mice. Ann Nutr Metab 27:26–37
Matsuda D, Tomoda H (2007) DGAT inhibitors for obesity. Curr Opin Investig Drugs 8:836–841
Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119
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 415:339–343
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 141:19–24
Mistry AM, Swick AG, Romsos DR (1997) Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 127:2065–2072
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 13:757–766
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–S15
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 53:931–938
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 266:24053–24058
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 46:357–363
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 10:3721–3727
Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444–E452
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 56:848–856
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 374:99–105
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 102:1384–1389
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 269:540–543
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:R790–795
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 78:1568–1578
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 92:865–872
Ritchie SA, Connell JM (2007) The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis 17:319–326
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 140:3688–3692
Rucker D, Padwal R, Li SK, Curioni C, Lau DC (2007) Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335:1194–1199
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 111:19–25
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 72:1359–1368
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 58:895–903
Schiffelers SL, Brouwer EM, Saris WH, van Baak MA (1998) Inhibition of lipolysis reduces β1-adrenoceptor-mediated thermogenesis in man. Metabolism 47:1462–1467
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 87:977–981
Schiffelers SL, Blaak EE, Saris WH, van Baak MA (2000) In vivo β3-adrenergic stimulation of human thermogenesis and lipid use. Clin Pharmacol Ther 67:558–566
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 86:2191–2199
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 25:33–38
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 49:2086–2096
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 274:24202–24210
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 56:348–358
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 285:1084–1095
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 47:1274–1280
Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76
Sivitz WI, Walsh SA, Morgan DA, Thomas MJ, Haynes WG (1997) Effects of leptin on insulin sensitivity in normal rats. Endocrinology 138:3395–3401
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 177–189
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 577:539–544
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–E600
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 33:574–587
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 36:239–262
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 22:923–926
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 321:642–647
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 100:15924–15929
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 49:1709–1713
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 35:769–776
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 42:377–385
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 320:1–13
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 71:272–279
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 S41–32
Vrydag W, Michel MC (2007) Tools to study β3-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 374:385–398
Wang M (2006) Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 for the treatment of metabolic syndrome. Curr Opin Investig Drugs 7:319–323
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 113:159–170
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 49:1333–1337
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 6:2
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 47:1555–1561
Wheeldon NM, McDevitt DG, Lipworth BJ (1993) Do β3-adrenoceptors mediate metabolic responses to isoprenaline. Q J Med 86:595–600
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 30:259–262
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 100:309–319
Wilson S, Arch JRS, Thurlby PL (1984b) Genetically obese C57BL/6 ob/ob mice respond normally to sympathomimetic compounds. Life Sci 35:1301–1309
Wilson S, Thurlby PL, Arch JR (1986) Substrate supply for thermogenesis induced by the β-adrenoceptor agonist BRL 26830A. Can J Physiol Pharmacol 65:113–119
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 279:214–221
Wing RR, Phelan S (2005) Long-term weight loss maintenance. Am J Clin Nutr 82:222S–225S
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 48:671–676
Yen TT, McKee MM, Bemis KG (1981) Ephedrine reduces weight of viable yellow obese mice (Avy/a). Life Sci 28:119–128
Yu YH, Ginsberg HN (2004) The role of acyl-CoA:diacylglycerol acyltransferase (DGAT) in energy metabolism. Ann Med 36:252–261
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 277:50230–50236
Zhan S, Ho SC (2005) Meta-analysis of the association of the Trp64Arg polymorphism in the β3 adrenergic receptor with insulin resistance. Obes Res 13:1709–1719
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):380–383
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–E657
Acknowledgements
The author thanks his many colleagues and collaborators in his work on β3-adrenoceptor agonists, notably Mike Cawthorne, Shelagh Wilson, John Clapham and Alberto Kaumann. He thanks Kenneth Langlands, Rob Ward, Don Smyth, Matthew Coghlan and Julie Cakebread for assistance in the preparation of this manuscript, and Frederic Preitner and Cedric Asensio for helpful discussions.
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This article is dedicated to Professor Hans Zaagsma in recognition of his contribution to the discovery of the β3-adrenoceptor.
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Arch, J.R.S. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists. Naunyn-Schmied Arch Pharmacol 378, 225–240 (2008). https://doi.org/10.1007/s00210-008-0271-1
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DOI: https://doi.org/10.1007/s00210-008-0271-1