Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Effects of Trecadrine®, a β3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes

International Journal of Obesity volume 26, pages 912–919 (2002)Cite this article

Abstract

Objective: Leptin, a hormone produced in adipocytes, is a key signal in the regulation of food intake and energy expenditure. β-Adrenergic agonists have been shown to inhibit leptin gene expression and leptin secretion. The mechanisms underlying the inhibitory effects of β-adrenergic agonists have not been established. In this study, we examined the effects of Trecadrine®, a novel β3-adrenergic agonist, on basal and insulin-stimulated leptin secretion in isolated rat adipocytes. Because insulin-stimulated glucose metabolism is an important regulator of leptin expression and secretion by the adipocytes, the effects of Trecadrine on indices of adipocyte metabolism were also examined.

Measurements: Isolated adipocytes were incubated with Trecadrine (10−8–10−4 M) in the absence or presence of insulin (1.6 nM). Leptin secretion, glucose utilization, lactate production, glucose incorporation into CO2 and triglyceride, as well as lipolysis (glycerol release) were determined.

Results: Trecadrine induced a concentration-dependent inhibition of basal leptin secretion. Trecadrine also decreased insulin-stimulated leptin secretion; however, the effect was not as pronounced as in the absence of insulin. Treatment of adipocytes with Trecadrine increased basal glucose utilization and produced a further increase in insulin-stimulated glucose utilization. Basal lactate production was also increased by Trecadrine; however, the proportion (percentage) of glucose carbon released as lactate was unaffected. In the presence of insulin, absolute lactate production was unaffected by Trecadrine at 96 h. However, the percentage of glucose carbon released as lactate was significantly decreased by insulin treatment, and was further decreased by the co-treatment with Trecadrine. Trecadrine induced a dose-dependent increase of the absolute amount of glucose incorporated into triglyceride. However, the percentage of glucose utilized that was incorporated into triglyceride was unaffected by Trecadrine. Trecadrine did not modify the proportion of glucose utilized that was oxidized to CO2. Trecadrine increased glycerol release after 96 h of treatment. Glycerol release was negatively correlated with leptin secretion.

Conclusions: These results suggest that alterations of glucose metabolism are not directly involved in the effects of β3-adrenergic agonists to inhibit leptin expression and secretion. The inverse relationship between leptin secretion and the increase of glycerol levels, which is an index of the activation of cAMP-dependent protein kinases, suggests that activation of the cAMP signaling pathway mediates the inhibitory effects of Trecadrine on leptin gene expression and secretion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Weise M, Frishman WH, Michaelson MD, Abdeen MA . The pharmacological approach to the treatment of obesity J Clin Pharmacol 1997 37: 453–473.

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Barrionuevo M, Milagro FI, Cenarruzabeitia E, Martínez JA . Potential anti-diabetic applications of a new molecule with affinity for β3-adrenoceptors Life Sci 1996 59: PL141–PL146.

    Article  CAS  PubMed  Google Scholar 

  4. Milagro FI, Gómez-Ambrosi J, Martínez-Ansó E, Martínez JA . Efffect of a β3-agonist on liver glucokinase gene expression in alloxan-diabetic rats J Physiol Biochem 1999 55: 25–32.

    CAS  PubMed  Google Scholar 

  5. Milagro FI, Gómez-Ambrosi J, Forga L, Martínez JA . A β3-adrenergic agonist increases muscle GLUT1/GLUT4 ratio, and regulates liver glucose utilization in diabetic rats Diabetes, Obes Metab 1999 1: 97–104.

    Article  CAS  Google Scholar 

  6. Berraondo B, Bonafonte A, Fernández-Otero MP, Martinez JA . Effects on energy utilization of a β3-adrenergic agonist in rats fed on a cafeteria diet Eating Weight Disord 1997 2: 130–137.

    Article  CAS  Google Scholar 

  7. Berraondo B, Marti A, Duncan JS, Trayhurn P, Martínez JA . Up-regulation of muscle UCP2 gene expression by a new beta-3 adrenoceptor agonist, tracadrine, in obese (cafeteria) rodents, but down-regulation in lean animals Int J Obes Relat Metab Disord 2000 24: 156–163.

    Article  CAS  PubMed  Google Scholar 

  8. Mantzoros CS, Qu D, Friederich RC, Susulic VS, Lowell BB, Maratos-Flier E, Flier JS . Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice Diabetes 1996 45: 909–914.

    Article  CAS  PubMed  Google Scholar 

  9. Trayhurn P, Duncan JS, Rayner DV, Hardie LJ . Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the β3-adrenoceptor agonist BRL 35135A and ZD2079 Biochem Biophys Res Commun 1996 228: 605–610.

    Article  CAS  PubMed  Google Scholar 

  10. Li H, Matheny M, Scarpace PJ . β3-Adrenergic-mediated suppression of leptin gene expression in rats Am J Physiol 1997 272: E1031–E1036.

    CAS  PubMed  Google Scholar 

  11. Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havel PJ . Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes Endocrinology 1998 139: 551–558.

    Article  CAS  PubMed  Google Scholar 

  12. Wellhoener P, Fruehwald-Schultes B, Kern W, Dantz D, Kerner W, Born J, Fehm HL, Peters A . Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans J Clin Endocrinol Metab 2000 85: 1267–1271.

    Article  CAS  PubMed  Google Scholar 

  13. Havel PJ . Role of adipose tissue in body-weight regulation: mechanisms regarding leptin production and energy balance Proc Nutr Soc 2000 59: 359–371.

    Article  CAS  PubMed  Google Scholar 

  14. Havel PJ . Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis Exp Biol Med 2001 226: 963–977.

    Article  CAS  Google Scholar 

  15. Havel PJ . Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulation protein, and adiponectin Curr Opin Lipidol 2002 13: 51–59.

    Article  CAS  PubMed  Google Scholar 

  16. Rentsch J, Chiesi M . Regulation of ob gene mRNA levels in cultured adipocytes FEBS Lett 1996 379: 55–59.

    Article  CAS  PubMed  Google Scholar 

  17. Shintani M, Nishimura H, Yonemitsu S, Masuzaki H, Ogawa Y, Hosoda K, Inoue G, Yoshimasa Y, Nakao K . Downregulation of leptin by free fatty acids in isolated rat adipocytes: effects of triacsin C, palmitate and bromopalmitate Metab Clin Exp 2000 49: 326–330.

    Article  CAS  PubMed  Google Scholar 

  18. Nonogaki K . New insights into sympathetic regulation of glucose and fat metabolism Diabetologia 2000 43: 533–549.

    Article  CAS  PubMed  Google Scholar 

  19. Landt M, Gingerich RL, Havel PJ, Mueller WM, Schoner B, Hale JE, Heiman ML . Radioimmunoassay of rat leptin: sexual dimorphism reversed from humans Clin Chem 1998 44: 565–570.

    CAS  PubMed  Google Scholar 

  20. Stanhope KL, Moreno-Aliaga MJ, Kras KM, Havel PJ . Assessment of lipogenesis in long-term cultured rat adipocytes, [Abstract.] Obes Res 1999 7: 74S.

    Google Scholar 

  21. Folch I, Lees M, Sloane-Stanley GH . A simple method for the isolation and purification of total lipids from animal tissue J Biol Chem 1957 193: 497–509.

    Google Scholar 

  22. Rodbell M . Metabolism of isolated fat cells. Effects of hormones on glucose metabolism and lipolysis J Biol Chem 1964 239: 375–380.

    CAS  PubMed  Google Scholar 

  23. Bottcher H, Furst P . Microcalorimetric and biochemical investigations of thermogenesis and metabolic pathways in human white adipocytes Int J Obes Relat Metab Disord 1996 20: 874–881.

    CAS  PubMed  Google Scholar 

  24. Gettys TW, Harness PJ, Watson PM . The β3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes Endocrinology 1996 137: 4054–4057.

    Article  CAS  PubMed  Google Scholar 

  25. Slieker LJ, Sloop KW, Surface PL, Kriaucinas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens TW . Regulation of expression of mRNA and protein by glucocorticoids and cAMP J Biol Chem 1996 271: 5301–5304.

    Article  CAS  PubMed  Google Scholar 

  26. Hardie LJ, Guilhot N, Trayhurn P . Regulation of leptin production in cultured mature white adipocytes Horm Metab Res 1996 28: 685–689.

    Article  CAS  PubMed  Google Scholar 

  27. Yoshida T, Hayashi M, Monkawa T, Saruta T . Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes Eur J Endocrinol 1996 135: 619–625.

    Article  CAS  PubMed  Google Scholar 

  28. Bradley R, Cheatham B . Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes Diabetes 1999 48: 272–278.

    Article  CAS  PubMed  Google Scholar 

  29. Fain JN, Cowan GS, Buffington C, Li J, Pouncey L, Bahouth SW . Syngergism between insulin and low concentrations of isoproterenol in the stimulation of leptin release by cultured human adipose tissue Metab Clin Exp 2000 49: 804–809.

    Article  CAS  PubMed  Google Scholar 

  30. Mueller WM, Stanhope KL, Gregoire F, Evans JL, Havel PJ . Effects of metformin and vanadium on leptin secretion from cultured rat adipocytes Obes Res 2000 8: 530–539.

    Article  CAS  PubMed  Google Scholar 

  31. Moreno-Aliaga MJ, Stanhope KL, Havel PJ . Transcriptional regulation of the leptin promoter by insulin-stimulated glucose metabolism in 3T3-L1 adipocytes Biochem Biophys Res Commun 2001 283: 544–548.

    Article  CAS  PubMed  Google Scholar 

  32. De Souza CJ, Hirshman MF, Horton ES . CL-316,243, a β3-specific adrenoceptor agonist, enhances insulin-stimulated glucose disposal in nonobese rats Diabetes 1997 46: 1257–1263.

    Article  CAS  PubMed  Google Scholar 

  33. Shimizu Y, Kielar D, Minokoshi Y, Shimazu T . Noradrenaline increases glucose transport into brown adipocytes in culture by a mechanisms different from that of insulin Biochem J 1996 314: 485–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Abe H, Minokoshi Y, Shimazu T . Effect of a β3-adrenergic agonist, BRL35135A, on glucose uptake in rat skeletal muscle in vivo and in vitro J Endocrinol 1993 139: 479–486.

    Article  CAS  PubMed  Google Scholar 

  35. Liu YL, Cawthorne MA, Stock MJ . Biophagic effects of the β-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle Br J Pharmac 1996 117: 1355–1361.

    Article  CAS  Google Scholar 

  36. Havel PJ, Stanhope KL, Moreno-Aliaga MJ, Kras KM, Evans J . Potential role for mitochondrial metabolism in regulating leptin production by cultured rat adipocytes. [Abstract.] Obes Res 1999 7: 63S.

    Google Scholar 

  37. Fain JN, Bahouth SW . Regulation of leptin release by mammalian adipose tissue Biochem Biophys Res Commun 2000 274: 571–575.

    Article  CAS  PubMed  Google Scholar 

  38. Lipworth BJ . Clinical pharmacology of β3-adrenoceptors J Clin Pharmacol 1996 42: 219–230.

    Google Scholar 

  39. Langin D, Holm C, Lafontan M . Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism Proc Nutr Soc 1996 55: 93–109.

    Article  CAS  PubMed  Google Scholar 

  40. Berraondo B, Martínez JA . Free fatty acids are involved in the inverse relationship between hormone-sensitive lipase (HSL) activity and expression in adipose tissue after high-fat feeding or β3-adrenergic stimulation Obes Res 2000 8: 255–261.

    Article  CAS  PubMed  Google Scholar 

  41. Wang MY, Lee Y, Unger RH . Novel form of lipolysis induced by leptin J Biol Chem 1999 274: 17541–17544.

    Article  CAS  PubMed  Google Scholar 

  42. Fukuda H, Iritani N . Transcriptional regulation of leptin gene promoter in rats FEBS Lett 1999 455: 165–169.

    Article  CAS  PubMed  Google Scholar 

  43. Soeder KJ, Snedden SK, Cao W, Della Rocca GJ, Daniel KW, Luttrell LM, Collins S . The β3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through Gi-dependent mechanism J Biol Chem 1999 274: 12017–12022.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH grants DK-50129 and DK-35747, the American Diabetes Association, the United States Department of Agriculture, Linea Especial Investigación ‘Nutrición, salud y obesidad’ (Universidad de Navarra) and the US-Spain Science and Technology Program 2000. MJ Moreno-Aliaga was supported by a Postdoctoral Fellowship from Ministerio de Educación y Cultura (Spain). Trecadrine was a gift from Wassermann-Chiesi (Barcelona/Milano).

Author information

Authors and Affiliations

  1. Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain

    MJ Moreno-Aliaga, JA Martínez & MP Fernández-Otero

  2. Department of Nutrition, University of California, Davis, One Shields Ave, Davis, California, USA

    KL Stanhope & PJ Havel

Authors
  1. MJ Moreno-Aliaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JA Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. KL Stanhope
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. MP Fernández-Otero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. PJ Havel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to PJ Havel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moreno-Aliaga, M., Martínez, J., Stanhope, K. et al. Effects of Trecadrine®, a β3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes. Int J Obes 26, 912–919 (2002). https://doi.org/10.1038/sj.ijo.0802003

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802003

Keywords

This article is cited by

Search

Advanced search

Quick links