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4-oxo-1,4-dihydrocinnoline Derivative with Phosphatase 1B Inhibitor Activity Enhances Leptin Signal Transduction in Hypothalamic Neurons

  • I. O. Zakharova
  • V. N. Sorokoumov
  • L. V. Bayunova
  • K. V. Derkach
  • A. O. Shpakov
Comparative and Ontogenic Biochemistry
  • 9 Downloads

Abstract

Most of regulatory effects of leptin on feeding behavior and energy metabolism are implemented via the hypothalamic leptin system. Attenuation of its activity leads to hyperphagia, obesity and other metabolic disorders. To prevent these pathological conditions, it is necessary to develop approaches aimed at restoring the leptin system. Most promising of them is creating efficient inhibitors of protein phosphotyrosine phosphatase PTP1B, a negative regulator of leptin signaling. The aim of this work was to synthesize a new compound, ethyl-3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline-6-carboxylate (PI-04), a 4-oxo-1,4-dihydrocinnoline derivative with a PTP1B inhibitor activity, and to study its effect on IRS2- and STAT3-dependent leptin pathways in culture of hypothalamic neurons isolated from 18-day-old rat embryos. It was shown that PI-04 enhances the stimulatory effect of leptin on phosphorylation of the IRS2 protein at the Ser731 residue and of the STAT3 transcriptional factor at the Tyr705 residue, suggesting a potentiation of functional responses of hypothalamic neurons to leptin in the presence of this compound. The potentiating effect of PI-04 on leptin signaling was implemented at micromolar concentrations when this substance had virtually no effect on neuronal survival. The data obtained are promising in terms of creating phosphatase PTP1B inhibitors based on 4-oxo-1,4-dihydrocinnoline, as well as the possibility of their further use to prevent and correct metabolic disorders caused by attenuated activity of the hypothalamic leptin system.

Key words

protein phosphotyrosine phosphatase 1B leptin receptor leptin hypothalamic neuron 4-oxo-1,4-dihydrocinnoline AKT-kinase STAT3 transcription factor 

Abbreviations

LepR

leptin receptor

MTT

3-(4,5-dimethylthiazol)-2,5-diphenyl-2-tetrazolium bromide

AKT

serine/threonine protein kinase B (AKT-kinase)

PTP1B

protein phosphotyrosine phosphatase 1B

STAT3 and STAT5

signal transducers and type 3 and 5 transcriptional activators

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References

  1. 1.
    Friedman, J.M. and Halaas, J.L., Leptin and the regulation of body weight in mammals, Nature, 1998, vol. 395, pp. 763–770.CrossRefGoogle Scholar
  2. 2.
    Zhou, Y. and Rui, L., Leptin signaling and leptin resistance, Front. Med., 2013, vol. 7, pp. 207–222.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Shpakov, A.O., Derkach, K.V., and Berstein, L.M., Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases, Future Science OA(FSO), 2015, vol. 1, FSO25. doi: 10.4155/fso.15.23Google Scholar
  4. 4.
    Morris, D.L. and Rui, L., Recent advances in understanding leptin signaling and leptin resistance, Am. J. Physiol., 2009, vol. 297, pp. 1247–1259.Google Scholar
  5. 5.
    Myers, M.G., Leibel, R.L., Seeley, R.J., and Schwartz, M.W., Obesity and leptin resistance: distinguishing cause from effect, Trends Endocrinol. Metab., 2010, vol. 21, pp. 643–651.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    El-Haschimi, K., Pierroz, D.D., Hileman, S.M., Bjorbaek, C., and Flier, J.S., Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity, J. Clin. Invest., 2000, vol. 105, pp. 1827–1832.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Banks, W.A. and Farrell, C.L., Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible, Am. J. Physiol., 2003, vol. 285, pp. 10–15.Google Scholar
  8. 8.
    Belouzard, S., Delcroix, D., and Rouille, Y., Low levels of expression of leptin receptor at the cell surface result from constitutive endocytosis and intracellular retention in the biosynthetic pathway, J. Biol. Chem., 2004, vol. 279, pp. 28 499–28 508.CrossRefGoogle Scholar
  9. 9.
    Hosoi, T., Sasaki, M., Miyahara, T., Hashimoto, C., Matsuo, S., Yoshii, M., and Ozawa, K., Endoplasmic reticulum stress induces leptin resistance, Mol. Pharmacol., 2008, vol. 74, pp. 1610–1619.CrossRefPubMedGoogle Scholar
  10. 10.
    Coppari, R. and Bjorbaek, C., Leptin revisited: its mechanism of action and potential for treating diabetes, Nat. Rev. Drug Discov., 2012, vol. 11, pp. 692–708.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Cheng, A., Uetani, N., Simoncic, P.D., Chaubey, V.P., Lee-Loy, A., McGlade, C.J., Kennedy, B.P., and Tremblay, M.L., Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B, Dev. Cell, 2002, vol. 2, pp. 497–503.CrossRefPubMedGoogle Scholar
  12. 12.
    Bence, K.K., Delibegovic, M., Xue, B., Gorgun, C.Z., Hotamisligil, G.S., Neel, B.G., and Kahn, B.B., Neuronal PTP1B regulates body weight, adiposity and leptin action, Nat. Med., 2006, vol. 12, pp. 917–924.PubMedGoogle Scholar
  13. 13.
    Loh, K., Fukushima, A., Zhang, X., Galic, S., Briggs, D., Enriori, P.J., Simonds, S., Wiede, F., Reichenbach, A., Hauser, C., Sims, N.A., Bence, K.K., Zhang, S., Zhang, Z.Y., Kahn, B.B., Neel, B.G., Andrews, Z.B., Cowley, M.A., and Tiganis, T., Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance, Cell. Metab., 2011, vol. 14, pp. 684–699.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Tsou, R.C. and Bence, K.K., Central regulation of metabolism by protein tyrosine phosphatases, Front. Neurosci., 2013, vol. 6, p. 192.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Kaszubska, W., Falls, H.D., Schaefer, V.G., Haasch, D., Frost, L., Hessler, P., Kroeger, P.E., White, D.W., Jirousek, M.R., and Trevillyan, J.M., Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line, Mol. Cell. Endocrinol., 2002, vol. 195, pp. 109–118.CrossRefPubMedGoogle Scholar
  16. 16.
    Tsou, R.C., Zimmer, D.J., De Jonghe, B.C., and Bence, K.K., Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice, Endocrinology, 2012, vol. 153, pp. 4227–4237.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Cho, H., Protein tyrosine phosphatase 1B (PTP1B) and obesity, Vitam. Horm., 2013, vol. 91, pp. 405–424.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang, S. and Zhang, Z.Y., PTP1B as a drug target: recent developments in PTP1B inhibitor discovery, Drug Discov. Today, 2007, vol. 12, pp. 373–381.CrossRefPubMedGoogle Scholar
  19. 19.
    Sorokoumov, V.N. and Shpakov, A.O., Protein phosphotyrosine phosphatase 1B: structure, functions, role in the development of metabolic disorders, and their correction by the enzyme inhibitors, J. Evol. Biochem. Physiol., 2017, vol. 53, no. 4, pp. 259–270.CrossRefGoogle Scholar
  20. 20.
    Zhi, Y., Gao, L.X., Jin, Y., Tang, C.L., Li, J.Y., Li, J., and Long, Y.Q., 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B, Bioorg. Med. Chem., 2014, vol. 22, pp. 3670–3683.CrossRefPubMedGoogle Scholar
  21. 21.
    Bakke, J. and Haj, F.G., Protein-tyrosine phosphatase 1B substrates and metabolic regulation, Semin. Cell Dev. Biol., 2015, vol. 37, pp. 58–65.CrossRefPubMedGoogle Scholar
  22. 22.
    Shpakov, A.O., The brain leptin signaling system and its functional state in metabolic syndrome and type 2 diabetes mellitus, J. Evol. Biochem. Physiol., 2016, vol. 52, no. 3, pp. 177–195.CrossRefGoogle Scholar
  23. 23.
    Bhattarai, B.R., Kafle, B., Hwang, J.-S., Ham, S.W., Lee, K.-H., Park, H., Han, I.O., and Cho, H., Novel thiazolidine dione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-? activators, Bioorg. Med. Chem. Lett., 2010, vol. 20, pp. 6758–6763.CrossRefPubMedGoogle Scholar
  24. 24.
    Ito, M., Fukuda, S., Sakata, S., Morinaga, H., and Ohta, T., Pharmacological effects of JTT-551, a novel protein tyrosine phosphatase 1B inhibitor, in diet-induced obesity mice, J. Diabetes Res., 2014, vol. 2014. doi: 10.1155/2014/680348Google Scholar
  25. 25.
    Niswender, K.D., Morton, G.J., Stearns, W.H., Rhodes, C.J., Myers, M.G., Jr., and Schwartz, M.W., Intracellular signalling. Key enzyme in leptin-induced anorexia, Nature, 2001, vol. 413, pp. 794–795.CrossRefPubMedGoogle Scholar
  26. 26.
    Lin, X., Taguchi, A., Park, S., Kushner, J.A., Li, F., Li, Y., and White, M.F., Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes, J. Clin. Invest., 2004, vol. 114, pp. 908–916.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Jiang, L., You, J., Yu, X., Gonzalez, L., Yu, Y., Wang, Q., Yang, G., Li, W., Li, C., and Liu, Y., Tyrosine-dependent and-independent actions of leptin receptor in control of energy balance and glucose homeostasis, Proc. Natl. Acad. Sci. USA, 2008, vol. 105, pp. 18 619–18 624.CrossRefGoogle Scholar
  28. 28.
    Piper, M.L., Unger, E.K., Myers, M.G., Jr., and Xu, A.W., Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons, Mol. Endocrinol., 2008, vol. 22, pp. 751–759.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • I. O. Zakharova
    • 1
  • V. N. Sorokoumov
    • 1
    • 2
  • L. V. Bayunova
    • 1
  • K. V. Derkach
    • 1
  • A. O. Shpakov
    • 1
  1. 1.Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia
  2. 2.St. Petersburg State UniversitySt. PetersburgRussia

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