Anti-Obesity Effects of Selective Agonists to the β3-Adrenergic Receptor in Dogs. II. Recruitment of Thermogenic Brown Adipocytes and Reduction of Adiposity after Chronic Treatment with a β3-Adrenergic Agonist
The aim of this study was to evaluate the effectiveness of β3-adrenergic agonists for the treatment and prevention of obesity in the dog. When a selective β3-adrenergic agonist, CL316, 243 (0.1 mg/kg), was given orally to adult beagles every day for 5-7 weeks, body weight and girth were decreased co...
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| Published in | Journal of Veterinary Medical Science Vol. 60; no. 4; pp. 465 - 469 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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JAPANESE SOCIETY OF VETERINARY SCIENCE
1998
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| Abstract | The aim of this study was to evaluate the effectiveness of β3-adrenergic agonists for the treatment and prevention of obesity in the dog. When a selective β3-adrenergic agonist, CL316, 243 (0.1 mg/kg), was given orally to adult beagles every day for 5-7 weeks, body weight and girth were decreased compared with control placebo-treated dogs. Gross anatomical examinations revealed no noticeable abnormalities in CL316, 243-treated dogs, except an apparent decrease in abdominal fat. Immunohistochemical examination of perirenal adipose tissue showed a remarkable increase in brown adipocytes expressing a thermogenic protein, uncoupling protein (UCP). The increased expression of UCP and its mRNA in CL316, 243-treated dogs was also confirmed by Western blot and reverse transcription polymerase chain reaction analyses. It was concluded that treatment with a β3-adrenergic agonist stimulates UCP expression, which may lead to an increase in energy expenditure, and thereby is useful for the treatment and prevention of obesity in the dog. |
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| AbstractList | The aim of this study was to evaluate the effectiveness of β3-adrenergic agonists for the treatment and prevention of obesity in the dog. When a selective β3-adrenergic agonist, CL316, 243 (0.1 mg/kg), was given orally to adult beagles every day for 5-7 weeks, body weight and girth were decreased compared with control placebo-treated dogs. Gross anatomical examinations revealed no noticeable abnormalities in CL316, 243-treated dogs, except an apparent decrease in abdominal fat. Immunohistochemical examination of perirenal adipose tissue showed a remarkable increase in brown adipocytes expressing a thermogenic protein, uncoupling protein (UCP). The increased expression of UCP and its mRNA in CL316, 243-treated dogs was also confirmed by Western blot and reverse transcription polymerase chain reaction analyses. It was concluded that treatment with a β3-adrenergic agonist stimulates UCP expression, which may lead to an increase in energy expenditure, and thereby is useful for the treatment and prevention of obesity in the dog. |
| Author | YOSHIDA, Toshihide SAITO, Masayuki UCHIDA, Eiji SASAKI, Noriyasu NIIYAMA, Masayoshi |
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| Copyright | 1998 by the Japanese Society of Veterinary Science |
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| References | 11. Krief, S., Lönqvist, F., Raimbault, S., Baude, B., Van Spronsen, A., Arner, P., Strosberg, A. D., Ricquier, D. and Emorine, L. J. 1993. Tissue distribution of β3-adrenergic receptor mRNA in man. J. Clin. Invest. 91: 344-349. 18. Nagase, I., Yoshida, T., Kumamoto, K., Umekawa, T., Sakane, N., Nikami, H., Kawada, T. and Saito, M. 1994. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic β3-adrenergic agonist. J. Clin. Invest. 97: 2898-2904. 7. Granneman, J. G., Lahness, K. N. and Chaudhry, A. 1991. Molecular cloning and expression of the rat β3-adrenergic receptor. Mol. Pharmacol. 40: 895-899. 15. Lowry, O. H., Rosebrough, A. L., Farr, A. L. and Randall, R. J. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193: 265-275. 16. Markwell, P. J., van Erk, W., Parkin, G. D., Sloth, C. J. and Shantz-Christienson, T. 1990. Obesity in the dog. J. Small Anim. Pract. 31: 533-537. 14. Lipworth, B. J. 1996. Clinical pharmacology of β3-adrenoceptors. Br. J. Clin. Pharmacol. 42: 291-300. 21. Rothwell, N. J. and Stock, M. J. 1979. A role of brown adipose tissue in diet-induced thermogenesis. Nature (Lond.) 281: 31. 12. Lafontan, M. and Berlan, M. 1993. Fat cell adrenergic receptors and the control of white and brown fat cell function. J. Lipid. Res. 34: 1057-1091. 5. Edney, A. T. B. and Smith, P. M. 1986. Study of obesity in dogs visiting veterinary practices in the United Kingdom. Vet. Rec. 118: 391-396. 23. Yoshida, T., Sakane, N., Wakabayashi, Y., Umekawa, T. and Kondo, M. 1994. Anti-obesity and anti-diabetic effects of CL316, 243, a highly specific β3-adrenoceptor agonist, in yellow KK mice. Life Sci. 54: 491-498. 17. Muzzin, P., Revelli, J. P., Kuhne, F., Gocayne, J. D., McCombie, W. R., Venter, J. C., Giacobino, J. P. and Fraser, C. M. 1991. An adipose tissue-specific β-adrenergic receptor. Molecular cloning and down-regulation in obesity. J. Biol. Chem. 266: 24053-24058. 20. Ricquier, D., Raimbault, S., Champigny, O., Miroux, B. and Bouillaud, F. 1992. The uncoupling protein is not expressed in rat liver. FEBS Lett. 303: 103-106. 3. Bouillaud, F., Raimbault, S. and Ricquier, D. 1988. The gene for rat uncoupling protein: complete sequence, structure of primary transcript and evolutionary relationship between exons. Biochem. Biophys. Res. Commun. 157: 783-792. 6. Emorine, L. J., Marullo, S., Briend-Sutren, M. M., Patey, G., Tate, K., Delavier-Klutchko, C. and Strosberg, A. D. 1989. Molecular characterization of the human β3-adrenergic receptor. Science 245: 1118-1121. 22. Sasaki, N., Uchida, E., Niiyama, M., Yoshida, T. and Saito, M. 1997. Anti-obesity effects of selective agonists to the β3-adrenergic receptor in dogs. I. The presence of canine β3-adrenergic receptor and in vivo lipomobilization by its agonists. J. Vet. Med. Sci. 60: 459-463. 4. Champigny, O., Ricquier, D., Blondel, O., Mayers, R. M., Briscoe, M. G. and Holloway, B.R. 1991. β3-Adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial uncoupling protein in adult dogs. Proc. Natl. Acad. Sci. U.S.A. 88: 10774-10777. 9. Klaus, S., Casteilla, L., Bouillaud, F. and Ricquier, D. 1991. The uncoupling protein UCP: a membranous mitochondrial ion carrier exclusively expressed in brown adipose tissue. Int. J. Biochem. 23: 791-801. 10. Klingenberg, M. 1990. Mechanism and evolution of the uncoupling protein of brown adipose tissue. Trends Biochem. Sci. 15: 108-112. 13. Langin, D., Portillo, M. P., Saulnier-Blache, J. S. and Lafontan, M. 1991. Coexistence of three β-adrenergic receptor subtypes in white fat cells of various mammalian species. Eur. J. Pharmacol. 199: 291-301. 19. Nahmias, C., Blin, N., Elalouf, J. M., Mattei, M. G., Strosberg, A. D. and Emorine, L. J. 1991. Molecular characterization of the mouse β3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J. 10: 3721-3727. 8. Himms-Hagen, J., Cui, J., Danforth. J., E., Taatjes, D. J., Lang, S. S., Waters, B. L. and Claus, T. H. 1994. Effect of CL-316, 243, a thermogenic β3-agonist, on energy balance and brown and white adipose tissues in rats. Am. J. Physiol. 266: R1371-R1382. 1. Arch, J. R. S., Ainsworth, A.T., Cawthorne, M.A., Piercy, V., Sennitt, M. V., Thody, V. E., Wilson, C. and Wilson, S. 1984. Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature (Lond.) 309: 163-165. 2. Bloom, J. D., Dutia, M. D., Johnson, B. D., Wissner, A., Burns, M. G., Largis, E. E., Dolan, J. A. and Claus, T. H. 1992. Disodium(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL316,243). A potent β-adrenergic agonist virtually specific for β3 receptors. A promising antidiabetic and antiobesity agent. J. Med. Chem. 35: 3081-3084. |
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| Title | Anti-Obesity Effects of Selective Agonists to the β3-Adrenergic Receptor in Dogs. II. Recruitment of Thermogenic Brown Adipocytes and Reduction of Adiposity after Chronic Treatment with a β3-Adrenergic Agonist |
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