Skip to main content
SpringerLink
Log in

Direct Effect of the Synthetic Analogue of Glucagon-Like Peptide Type 1, Liraglutide, on Mature Adipocytes Is Realized through Adenylate-Cyclase-Dependent Enhancing of Insulin Sensitivity

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Incretin hormones analogues, including glucagon-like peptide type 1 (GLP-1), exhibit complex glucose-lowering, anorexigenic, and cardioprotective properties. Mechanisms of action of GLP-1 and its analogues are well known for pancreatic β-cells, hepatocytes, and other tissues. Nevertheless, local effects of GLP-1 and its analogues in adipose tissue remain unclear. In the present work effects of the GLP-1 synthetic analogue, liraglutide, on adipogenesis and insulin sensitivity of the 3T3-L1 adipocytes were examined. Enhancement of insulin sensitivity of mature adipocytes by the GLP-1 synthetic analogue liraglutide mediated by adenylate cyclase was demonstrated. The obtained results imply existence of the positive direct insulin-sensitizing effect of liraglutide on mature adipocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

Abbreviations

CREB:

cAMP responsive element binding protein

GLP-1:

glucagon-like peptide-1

cAMP:

cyclic adenosine monophosphate

Erk:

extracellular signal regulated kinase

GLUT4:

glucose transporter type 4

IR:

insulin resistance

IRS-1:

insulin receptor substrate type 1

JNK:

c-Jun NH2-terminal kinase

PKA:

protein kinase A, cAMP-dependent protein kinase

PPARgamma:

peroxisome proliferator-activated receptor type gamma

SQ22536:

adenylate cyclase inhibitor

T2DM:

type 2 diabetes mellitus

UCP-1:

uncoupling protein type 1

References

  1. Olefsky, J. M., and Glass, C. K. (2010) Macrophages, inflammation, and insulin resistance, Annu. Rev. Physiol., 72, 219-246.

    Article  CAS  PubMed  Google Scholar 

  2. Vorotnikov, A. V., Stafeev, I. S., Menshikov, M. Yu., Shestakova, M. V., and Parfyonova, Ye. V. (2019) Latent inflammation and defect in adipocyte renewal as a mechanism of obesity-associated insulin resistance, Biochemistry (Moscow), 84, 1329-1345.

    Article  CAS  Google Scholar 

  3. Gallagher, E. J., and LeRoith, D. (2015) Obesity and diabetes: the increased risk of cancer and cancer-related mortality, Physiol. Rev., 95, 727-748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Booth, G. L., Kapral, M. K., Fung, K., and Tu, J. V. (2006) Recent trends in cardiovascular complications among men and women with and without diabetes, Diabetes Care, 29, 32-37.

    Article  PubMed  Google Scholar 

  5. Mojsov, S., Weir, G. C., and Habener, J. F. (1987) Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas, J. Clin. Invest., 79, 616-619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deacon, C. F., Nauck, M. A., Toft-Nielsen, M., Pridal, L., Willms, B., and Holst, J. J. (1995) Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects, Diabetes, 44, 1126-1131.

    Article  CAS  PubMed  Google Scholar 

  7. Jackson, S. H., Martin, T. S., Jones, J. D., Seal, D., and Emanuel, F. (2010) Liraglutide (victoza): the first once-daily incretin mimetic injection for type 2 diabetes, P T, 35, 498-529.

    PubMed  PubMed Central  Google Scholar 

  8. Chou, C. Y., Chang, Y. T., Yang, J. L., Wang, J. Y., Lee, T. E., et al. (2017) Effect of long-term incretin-based therapies on ischemic heart diseases in patients with type 2 diabetes mellitus: a network meta-analysis, Sci. Rep., 7, 15795.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Nathanson, D., Ullman, B., Löfström, U., Hedman, A., Frick, M., et al. (2012) Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety, Diabetologia, 55, 926-935.

    Article  CAS  PubMed  Google Scholar 

  10. White, W. B., and Baker, W. L. (2016) Cardiovascular effects of incretin-based therapies, Annu. Rev. Med., 67, 245-260.

    Article  CAS  PubMed  Google Scholar 

  11. Erdogdu, O., Nathanson, D., Sjöholm, A., Nyström, T., and Zhang, Q. (2010) Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor, Mol. Cell. Endocrinol., 325, 26-35.

    Article  CAS  PubMed  Google Scholar 

  12. Ding, W. G., and Gromada, J. (1997) Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide, Diabetes, 46, 615-621.

    Article  CAS  PubMed  Google Scholar 

  13. Knop, F. K., Visboll, T., and Holst, J. J. (2009) Incretin-based therapy of type 2 diabetes mellitus, Curr. Protein. Pept. Sci., 10, 46-55.

    Article  CAS  PubMed  Google Scholar 

  14. Campbell, J. E., and Drucker, D. J. (2013) Pharmacology, physiology and mechanisms of incretin hormone action, Cell. Metab., 17, 819-837.

    Article  CAS  PubMed  Google Scholar 

  15. Young, A. A., Gedulin, B. R., Bhavsar, S., Bodkin, N., Jodka, C., et al. (1999) Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta), Diabetes, 48, 1026-1034.

    Article  CAS  PubMed  Google Scholar 

  16. Challa, T. D., Beaton, N., Arnold, M., Rudofsky, G., Langhans, W., and Wolfrum, C. (2012) Regulation of adipocyte formation by GLP-1/GLP-1R signaling, J. Biol. Chem., 287, 6421-6430.

    Article  CAS  PubMed  Google Scholar 

  17. Chen, J., Zhao, H., Ma, X., Zhang, Y., Lu, S., et al. (2017) GLP-1/GLP-1R signaling in regulation of adipocyte differentiation and lipogenesis, Cell. Physiol. Biochem., 42, 1165-1176.

    Article  CAS  PubMed  Google Scholar 

  18. Vendrell, J., Bekay, R. E., Peral, B., García-Fuentes, E., Megia, A., et al. (2011) Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance, Endocrinology, 152, 4072-4079.

    Article  CAS  PubMed  Google Scholar 

  19. Zebisch, K., Voight, V., Wabitsch, M., and Brandsch, M. (2012) Protocol for effective differentiation of 3T3-L1 cells to adipocytes, Anal. Biochem., 425, 8890.

    Article  CAS  Google Scholar 

  20. Miller, C. N., Yang, J. Y., England, E., Yin, A., Baile, C. A., and Rayalam, S. (2015) Isoproterenol increases uncoupling, glycolysis, and markers of beiging in mature 3T3-L1 adipocytes, PLoS One, 10, e0138344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Laemmli, U. K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature, 15, 680-685.

    Article  Google Scholar 

  22. Bao, Y., Jiang, L., Chen, H., Zou, J., Liu, Z., and Shi, Y. (2015) The neuroprotective effect of liraglutide is mediated by glucagon-like peptide 1 receptor-mediated activation of cAMP/PKA/CREB pathway, Cell. Physiol. Biochem., 36, 2366-2378.

    Article  CAS  PubMed  Google Scholar 

  23. Kimura, T., Kaneto, H., Shimoda, M., Hirukawa, H., Okauchi, S., et al. (2015) Protective effects of pioglitazone and/or liraglutide on pancreatic β-cells in db/db mice: comparison of their effects between in an early and advanced stage of diabetes, Mol. Cell. Endocrinol., 400, 78-89.

    Article  CAS  PubMed  Google Scholar 

  24. Que, Q., Guo, X., Zhan, L., Chen, S., Zhang, Z., et al. (2019) The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis, J. Inflamm. (Lond), 16, 13.

    Article  CAS  Google Scholar 

  25. Haslam, R. J., Davidson, M. M., and Desjardins, J. V. (1978) Inhibition of adenylate cyclase by adenosine analogues in preparations of broken and intact human platelets. Evidence for the unidirectional control of platelet function by cyclic AMP, Biochem. J., 176, 83-95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Juan, C., Chang, C., Lai, Y., and Ho, L. (2005) Endothelin-1 induces lipolysis in 3T3-L1 adipocytes, Am. J. Physiol. Endocrinol. Metab., 288, E1146-E1152.

    Article  CAS  PubMed  Google Scholar 

  27. Li, F., Wang, D., Zhou, Y., Zhou, B., Yang, Y., et al. (2008) Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes, Cell. Res., 18, 311-323.

    Article  CAS  PubMed  Google Scholar 

  28. Wang, Q., and Brubacker, P. (2002) Glucagon-like peptide 1 treatment delays the onset of diabetes in 8 week-old db/db mice, Diabetologia, 45, 1263-1273.

    Article  CAS  PubMed  Google Scholar 

  29. Willard, F. S., and Sloop, K. W. (2012) Physiology and emerging biochemistry of the glucagon-like peptide-1 receptor, Exp. Diab. Res., 2012, 470851.

    Google Scholar 

  30. Cho, Y. M., Fujita, Y., and Kieffer, T. J. (2014) Glucagon-like peptide-1: glucose homeostasis and beyond, Annu. Rev. Physiol., 76, 533-536.

    Article  CAS  Google Scholar 

  31. Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J., and Meier, J. J. (2011) Secretion of glucagon-like peptide 1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia, 54, 10-18.

    Article  CAS  PubMed  Google Scholar 

  32. Woerle, H. J., Carneiro, L., Derani, A., Goke, B., and Schirra, J. (2012) The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes, Diabetes, 61, 2349-2358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahren, B. (2013) Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives, Diabetes. Metab., 39, 195-201.

    Article  CAS  PubMed  Google Scholar 

  34. Peters, A. (2010) Incretin-based therapies: review of current clinical trial data, Am. J. Med., 123, S28-S37.

    Article  CAS  PubMed  Google Scholar 

  35. Drucker, D. J., Sherman, S. I., Gorelick, F. S., Bergenstal, R. M., Sherwin, R. S., and Buse, J. B. (2010) Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefit, Diabetes Care, 33, 428-433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lockie, S. H., Heppner, K. M., Chaudhary, N., Chabenne, J. R., Morgan, D. A., et al. (2012) Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling, Diabetes, 61, 2753-2762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Beiroa, D., Imbernon, M., Gallego, R., Senra, A., Herranz, D., et al. (2014) GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK, Diabetes, 63, 3346-3358.

    Article  CAS  PubMed  Google Scholar 

  38. Kooijman, S., Wang, Y., Parlevliet, E. T., Boon, M. R., Edelschaap, D., et al. (2015) Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice, Diabetologia, 58, 2637-2646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ejarque, M., Guerrero-Pérez, F., de la Morena, N., Casajoana, A., Virgili, N., et al. (2019) Role of adipose tissue GLP-1R expression in metabolic improvement after bariatric surgery in patients with type 2 diabetes, Sci. Rep., 9, 6274.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Quoyer, J., Longuet, C., Broca, C., Linck, N., Costes, S., et al. (2010) GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a β-arrestin 1-mediated ERK1/2 activation in pancreatic β-cells, J. Biol. Chem., 285, 1989-2002.

    Article  CAS  PubMed  Google Scholar 

  41. Li, Y., Tweedie, D., Mattson, M. P., Holloway, H. W., and Greig, N. H. (2010) Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells, J. Neurochem., 113, 1621-1631.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shiraishi, D., Fujiwara, Y., Komohara, Y., Mizuta, H., and Takeya, M. (2012) Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation, Biochem. Biophys. Res. Commun., 425, 304-308.

    Article  CAS  PubMed  Google Scholar 

  43. Lee, Y. S., Park, M. S., Choung, J. S., Kim, S. S., et al. (2012) Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes, Diabetologia, 55, 2456-2468.

    Article  CAS  PubMed  Google Scholar 

  44. Gao, H., Wang, X., Zhang, Z., Yang, Y., Yang, J., et al. (2007) GLP-1 amplifies insulin signaling by up-regulation of IRbeta, IRS-1 and Glut4 in 3T3-L1 adipocytes, Endocrine, 32, 90-95.

    Article  CAS  PubMed  Google Scholar 

  45. Hai, T., and Curran, T. (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity, Proc. Natl. Acad. Sci. USA, 88, 3720-3724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The study was financially supported by the Russian Science Foundation (project no. 19-75-00068) and by the collaboration framework between the Russian Science Foundation and Ministry of Science and Technology of Taiwan (project no. 20-45-08003).

Author information

Authors and Affiliations

  1. Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Elizaveta D. Mamontova & Svetlana S. Michurina

  2. Institute of Experimental Cardiology, National Medical Research Centre for Cardiology, 121552, Moscow, Russia

    Elizaveta D. Mamontova, Svetlana S. Michurina, Iurii S. Stafeev, Mikhail Y. Menshikov & Yelena V. Parfyonova

  3. Diabetes Institute, Endocrinology Research Centre, 117036, Moscow, Russia

    Elizaveta D. Mamontova, Ekaterina L. Sorkina, Igor A. Sklyanik, Ekaterina O. Koksharova & Marina V. Shestakova

  4. Faculty of Basic Medicine, Lomonosov Moscow State University, 119234, Moscow, Russia

    Yelena V. Parfyonova

Authors
  1. Elizaveta D. Mamontova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Svetlana S. Michurina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Iurii S. Stafeev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ekaterina L. Sorkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Igor A. Sklyanik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ekaterina O. Koksharova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mikhail Y. Menshikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marina V. Shestakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yelena V. Parfyonova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iurii S. Stafeev.

Ethics declarations

Authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mamontova, E.D., Michurina, S.S., Stafeev, I.S. et al. Direct Effect of the Synthetic Analogue of Glucagon-Like Peptide Type 1, Liraglutide, on Mature Adipocytes Is Realized through Adenylate-Cyclase-Dependent Enhancing of Insulin Sensitivity. Biochemistry Moscow 86, 350–360 (2021). https://doi.org/10.1134/S000629792103010X

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629792103010X

Keywords

Search

Navigation