Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1997 Apr 15;323(Pt 2):359–364. doi: 10.1042/bj3230359

Down-regulation of beta3-adrenergic receptor expression in rat adipose tissue during the fasted/fed transition: evidence for a role of insulin.

K E Hadri 1, C Charon 1, J Pairault 1, S Hauguel-De Mouzon 1, A Quignard-Boulangé 1, B Fève 1
PMCID: PMC1218327  PMID: 9163324

Abstract

The beta3-adrenergic receptor (beta3-AR) exerts a central role in the transduction of catecholamine effects in white and brown adipose tissue (WAT and BAT). A recent report has documented that insulin strongly down-regulates beta3-AR expression and catecholamine responsiveness in 3T3-F442A adipocytes [Fève, El Hadri, Quignard-Boulangé and Pairault (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 5677-5681]. In the present report we show that the rise in plasma insulin levels elicited by the fasted/fed transition is associated with a reduction in beta3-AR mRNA levels and beta-adrenergic responsiveness in WAT and BAT. beta3-AR transcripts are also decreased in adipose tissue from animals subjected for 6 h to euglycaemic hyperinsulinaemic glucose clamps. Moreover, insulin acts directly on cultured rat white and brown adipocytes to decrease beta3-AR gene expression and adenylate cyclase activity in response to beta3-AR-selective agonists. These results suggest that there is a close relationship between food intake, plasma insulin levels and beta3-AR expression.

Full Text

The Full Text of this article is available as a PDF (281.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ailhaud G., Grimaldi P., Négrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr. 1992;12:207–233. doi: 10.1146/annurev.nu.12.070192.001231. [DOI] [PubMed] [Google Scholar]
  2. Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
  3. Antras J., Lasnier F., Pairault J. Beta-adrenergic-cyclic AMP signalling pathway modulates cell function at the transcriptional level in 3T3-F442A adipocytes. Mol Cell Endocrinol. 1991 Dec;82(2-3):183–190. doi: 10.1016/0303-7207(91)90030-v. [DOI] [PubMed] [Google Scholar]
  4. Arch J. R., Ainsworth A. T., Cawthorne M. A., Piercy V., Sennitt M. V., Thody V. E., Wilson C., Wilson S. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature. 1984 May 10;309(5964):163–165. doi: 10.1038/309163a0. [DOI] [PubMed] [Google Scholar]
  5. Arch J. R., Kaumann A. J. Beta 3 and atypical beta-adrenoceptors. Med Res Rev. 1993 Nov;13(6):663–729. doi: 10.1002/med.2610130604. [DOI] [PubMed] [Google Scholar]
  6. Barbe P., Millet L., Galitzky J., Lafontan M., Berlan M. In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue. Br J Pharmacol. 1996 Mar;117(5):907–913. doi: 10.1111/j.1476-5381.1996.tb15279.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blin N., Camoin L., Maigret B., Strosberg A. D. Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor. Mol Pharmacol. 1993 Dec;44(6):1094–1104. [PubMed] [Google Scholar]
  8. Boileau P., Mrejen C., Girard J., Hauguel-de Mouzon S. Overexpression of GLUT3 placental glucose transporter in diabetic rats. J Clin Invest. 1995 Jul;96(1):309–317. doi: 10.1172/JCI118036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  10. Briquet-Laugier V., Dugail I., Ardouin B., Le Liepvre X., Lavau M., Quignard-Boulangé A. Evidence for a sustained genetic effect on fat storage capacity in cultured adipose cells from Zucker rats. Am J Physiol. 1994 Sep;267(3 Pt 1):E439–E446. doi: 10.1152/ajpendo.1994.267.3.E439. [DOI] [PubMed] [Google Scholar]
  11. Carpéné C., Galitzky J., Collon P., Esclapez F., Dauzats M., Lafontan M. Desensitization of beta-1 and beta-2, but not beta-3, adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion. J Pharmacol Exp Ther. 1993 Apr;265(1):237–247. [PubMed] [Google Scholar]
  12. Charon C., Krief S., Diot-Dupuy F., Strosberg A. D., Emorine L. J., Bazin R. Early alterations in the brown adipose tissue adenylate cyclase system of pre-obese Zucker rat fa/fa pups: decreased G-proteins and beta 3-adrenoceptor activities. Biochem J. 1995 Dec 15;312(Pt 3):781–788. doi: 10.1042/bj3120781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Clément K., Vaisse C., Manning B. S., Basdevant A., Guy-Grand B., Ruiz J., Silver K. D., Shuldiner A. R., Froguel P., Strosberg A. D. Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med. 1995 Aug 10;333(6):352–354. doi: 10.1056/NEJM199508103330605. [DOI] [PubMed] [Google Scholar]
  16. Collins S., Daniel K. W., Rohlfs E. M., Ramkumar V., Taylor I. L., Gettys T. W. Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol Endocrinol. 1994 Apr;8(4):518–527. doi: 10.1210/mend.8.4.7914350. [DOI] [PubMed] [Google Scholar]
  17. De Gasquet P., Griglio S., Pequignot-Planche E., Malewiak M. I. Diurnal changes in plasma and liver lipids and lipoprotein lipase activity in heart and adipose tissue in rats fed a high and low fat diet. J Nutr. 1977 Feb;107(2):199–212. doi: 10.1093/jn/107.2.199. [DOI] [PubMed] [Google Scholar]
  18. El Hadri K., Fève B., Pairault J. Developmental expression and functional activity of beta 1- and beta 3-adrenoceptors in murine 3T3-F442A differentiating adipocytes. Eur J Pharmacol. 1996 Feb 15;297(1-2):107–119. doi: 10.1016/0014-2999(95)00723-7. [DOI] [PubMed] [Google Scholar]
  19. Engfeldt P., Hellmér J., Wahrenberg H., Arner P. Effects of insulin on adrenoceptor binding and the rate of catecholamine-induced lipolysis in isolated human fat cells. J Biol Chem. 1988 Oct 25;263(30):15553–15560. [PubMed] [Google Scholar]
  20. Enocksson S., Shimizu M., Lönnqvist F., Nordenström J., Arner P. Demonstration of an in vivo functional beta 3-adrenoceptor in man. J Clin Invest. 1995 May;95(5):2239–2245. doi: 10.1172/JCI117914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Foufelle F., Gouhot B., Perdereau D., Girard J., Ferre P. Regulation of lipogenic enzyme and phosphoenolpyruvate carboxykinase gene expression in cultured white adipose tissue. Glucose and insulin effects are antagonized by cAMP. Eur J Biochem. 1994 Aug 1;223(3):893–900. doi: 10.1111/j.1432-1033.1994.tb19066.x. [DOI] [PubMed] [Google Scholar]
  22. Fève B., Baude B., Krief S., Strosberg A. D., Pairault J., Emorine L. J. Inhibition by dexamethasone of beta 3-adrenergic receptor responsiveness in 3T3-F442A adipocytes. Evidence for a transcriptional mechanism. J Biol Chem. 1992 Aug 5;267(22):15909–15915. [PubMed] [Google Scholar]
  23. Fève B., Elhadri K., Quignard-Boulangé A., Pairault J. Transcriptional down-regulation by insulin of the beta 3-adrenergic receptor expression in 3T3-F442A adipocytes: a mechanism for repressing the cAMP signaling pathway. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5677–5681. doi: 10.1073/pnas.91.12.5677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fève B., Emorine L. J., Lasnier F., Blin N., Baude B., Nahmias C., Strosberg A. D., Pairault J. Atypical beta-adrenergic receptor in 3T3-F442A adipocytes. Pharmacological and molecular relationship with the human beta 3-adrenergic receptor. J Biol Chem. 1991 Oct 25;266(30):20329–20336. [PubMed] [Google Scholar]
  25. Fève B., Piétri-Rouxel F., el Hadri K., Drumare M. F., Strosberg A. D. Long term phorbol ester treatment down-regulates the beta 3-adrenergic receptor in 3T3-F442A adipocytes. J Biol Chem. 1995 May 5;270(18):10952–10959. doi: 10.1074/jbc.270.18.10952. [DOI] [PubMed] [Google Scholar]
  26. Girard J., Perdereau D., Foufelle F., Prip-Buus C., Ferré P. Regulation of lipogenic enzyme gene expression by nutrients and hormones. FASEB J. 1994 Jan;8(1):36–42. doi: 10.1096/fasebj.8.1.7905448. [DOI] [PubMed] [Google Scholar]
  27. Granneman J. G. Effects of agonist exposure on the coupling of beta 1 and beta 3 adrenergic receptors to adenylyl cyclase in isolated adipocytes. J Pharmacol Exp Ther. 1992 May;261(2):638–642. [PubMed] [Google Scholar]
  28. Granneman J. G., Lahners K. N., Chaudhry A. Characterization of the human beta 3-adrenergic receptor gene. Mol Pharmacol. 1993 Aug;44(2):264–270. [PubMed] [Google Scholar]
  29. Granneman J. G., Lahners K. N. Differential adrenergic regulation of beta 1- and beta 3-adrenoreceptor messenger ribonucleic acids in adipose tissues. Endocrinology. 1992 Jan;130(1):109–114. doi: 10.1210/endo.130.1.1309320. [DOI] [PubMed] [Google Scholar]
  30. Granneman J. G., MacKenzie R. G. Neural modulation of the stimulatory regulatory protein of adenylate cyclase in rat brown adipose tissue. J Pharmacol Exp Ther. 1988 Jun;245(3):1068–1074. [PubMed] [Google Scholar]
  31. Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J. 1990 Aug;4(11):2890–2898. [PubMed] [Google Scholar]
  32. Koopmans S. J., De Boer S. F., Radder J. K., Frölich M., Krans H. M. Counterregulatory hormone responses during graded hyperinsulinemic euglycemia in conscious rats. Physiol Behav. 1993 Dec;54(6):1141–1148. doi: 10.1016/0031-9384(93)90338-g. [DOI] [PubMed] [Google Scholar]
  33. Krief S., Fève B., Baude B., Zilberfarb V., Strosberg A. D., Pairault J., Emorine L. J. Transcriptional modulation by n-butyric acid of beta 1-, beta 2-, and beta 3-adrenergic receptor balance in 3T3-F442A adipocytes. J Biol Chem. 1994 Mar 4;269(9):6664–6670. [PubMed] [Google Scholar]
  34. Krief S., Lönnqvist F., Raimbault S., Baude B., Van Spronsen A., Arner P., Strosberg A. D., Ricquier D., Emorine L. J. Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest. 1993 Jan;91(1):344–349. doi: 10.1172/JCI116191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lafontan M., Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 1993 Jul;34(7):1057–1091. [PubMed] [Google Scholar]
  36. Leturque A., Burnol A. F., Ferré P., Girard J. Pregnancy-induced insulin resistance in the rat: assessment by glucose clamp technique. Am J Physiol. 1984 Jan;246(1 Pt 1):E25–E31. doi: 10.1152/ajpendo.1984.246.1.E25. [DOI] [PubMed] [Google Scholar]
  37. Menéndez J. A., Atrens D. M. Insulin and the paraventricular hypothalamus: modulation of energy balance. Brain Res. 1991 Aug 2;555(2):193–201. doi: 10.1016/0006-8993(91)90342-s. [DOI] [PubMed] [Google Scholar]
  38. Nahmias C., Blin N., Elalouf J. M., Mattei M. G., Strosberg A. D., Emorine L. J. Molecular characterization of the mouse beta 3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J. 1991 Dec;10(12):3721–3727. doi: 10.1002/j.1460-2075.1991.tb04940.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nantel F., Bonin H., Emorine L. J., Zilberfarb V., Strosberg A. D., Bouvier M., Marullo S. The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol. 1993 Apr;43(4):548–555. [PubMed] [Google Scholar]
  40. Nantel F., Marullo S., Krief S., Strosberg A. D., Bouvier M. Cell-specific down-regulation of the beta 3-adrenergic receptor. J Biol Chem. 1994 May 6;269(18):13148–13155. [PubMed] [Google Scholar]
  41. Olansky L., Pohl S. L. beta-Adrenergic desensitization by chronic insulin exposure in 3T3-L1 cultured adipocytes. Metabolism. 1984 Jan;33(1):76–81. doi: 10.1016/0026-0495(84)90165-3. [DOI] [PubMed] [Google Scholar]
  42. Onai T., Kilroy G., York D. A., Bray G. A. Regulation of beta 3-adrenergic receptor mRNA by sympathetic nerves and glucocorticoids in BAT of Zucker obese rats. Am J Physiol. 1995 Sep;269(3 Pt 2):R519–R526. doi: 10.1152/ajpregu.1995.269.3.R519. [DOI] [PubMed] [Google Scholar]
  43. Paulauskis J. D., Sul H. S. Hormonal regulation of mouse fatty acid synthase gene transcription in liver. J Biol Chem. 1989 Jan 5;264(1):574–577. [PubMed] [Google Scholar]
  44. Raynolds M. V., Awald P. D., Gordon D. F., Gutierrez-Hartmann A., Rule D. C., Wood W. M., Eckel R. H. Lipoprotein lipase gene expression in rat adipocytes is regulated by isoproterenol and insulin through different mechanisms. Mol Endocrinol. 1990 Sep;4(9):1416–1422. doi: 10.1210/mend-4-9-1416. [DOI] [PubMed] [Google Scholar]
  45. Revelli J. P., Muzzin P., Giacobino J. P. Modulation in vivo of beta-adrenergic-receptor subtypes in rat brown adipose tissue by the thermogenic agonist Ro 16-8714. Biochem J. 1992 Sep 15;286(Pt 3):743–746. doi: 10.1042/bj2860743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Revelli J. P., Muzzin P., Paoloni A., Moinat M., Giacobino J. P. Expression of the beta 3-adrenergic receptor in human white adipose tissue. J Mol Endocrinol. 1993 Apr;10(2):193–197. doi: 10.1677/jme.0.0100193. [DOI] [PubMed] [Google Scholar]
  47. Rothwell N. J., Stock M. J. Insulin and thermogenesis. Int J Obes. 1988;12(2):93–102. [PubMed] [Google Scholar]
  48. Smith C. J., Manganiello V. C. Role of hormone-sensitive low Km cAMP phosphodiesterase in regulation of cAMP-dependent protein kinase and lipolysis in rat adipocytes. Mol Pharmacol. 1989 Mar;35(3):381–386. [PubMed] [Google Scholar]
  49. Susulic V. S., Frederich R. C., Lawitts J., Tozzo E., Kahn B. B., Harper M. E., Himms-Hagen J., Flier J. S., Lowell B. B. Targeted disruption of the beta 3-adrenergic receptor gene. J Biol Chem. 1995 Dec 8;270(49):29483–29492. doi: 10.1074/jbc.270.49.29483. [DOI] [PubMed] [Google Scholar]
  50. Tate K. M., Briend-Sutren M. M., Emorine L. J., Delavier-Klutchko C., Marullo S., Strosberg A. D. Expression of three human beta-adrenergic-receptor subtypes in transfected Chinese hamster ovary cells. Eur J Biochem. 1991 Mar 14;196(2):357–361. doi: 10.1111/j.1432-1033.1991.tb15824.x. [DOI] [PubMed] [Google Scholar]
  51. Thomas R. F., Holt B. D., Schwinn D. A., Liggett S. B. Long-term agonist exposure induces upregulation of beta 3-adrenergic receptor expression via multiple cAMP response elements. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4490–4494. doi: 10.1073/pnas.89.10.4490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Walston J., Silver K., Bogardus C., Knowler W. C., Celi F. S., Austin S., Manning B., Strosberg A. D., Stern M. P., Raben N. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med. 1995 Aug 10;333(6):343–347. doi: 10.1056/NEJM199508103330603. [DOI] [PubMed] [Google Scholar]
  53. Widén E., Lehto M., Kanninen T., Walston J., Shuldiner A. R., Groop L. C. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 1995 Aug 10;333(6):348–351. doi: 10.1056/NEJM199508103330604. [DOI] [PubMed] [Google Scholar]
  54. el Hadri K., Pairault J., Fève B. Triiodothyronine regulates beta 3-adrenoceptor expression in 3T3-F442A differentiating adipocytes. Eur J Biochem. 1996 Jul 15;239(2):519–525. doi: 10.1111/j.1432-1033.1996.0519u.x. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES