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Insulin receptors in mouse brain: Reversibility of age-related impairments by a thymic extract

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Abstract

Recently, we have shown that insulin receptors (InsRs) in the brain undergo impairments with aging. Interestingly, age-related alterations of brain InsRs, are not irreparable as thymus grafts are able to recover them. With the present study we verified the possibility that an aqueous extract from calf thymus (TME) can mimic the restoring action of age-related impairments induced by thymus graft. InsR characteristics were assayed in a group of 25 months old BALB/c-nu mice treated with TME: 2μg/g body weight every third day, for total five subcutaneous injections. The last dose was injected the day before animals were killed. Other two groups of young (4 months) and old (25 months) mice received saline solution with the same schedule. A two-sites model analysis of receptor data confirms the age-dependent decrease of InsR number and kd previously observed in the high affinity population. Furthermore, a statistically significant recovery of number impairment is shown in TME-treated animals. On the contrary, the characteristics of the low affinity receptor subset show no statistically significant differences among the three animal models studied. TME induced recovery of the age-related changes found in brain InsRs, together with previously observed regulatory action of the same thymic extract on the adrenergic system, suggest that thymic gland does not necessarily have to mutually interact with other controlling systems for maintaining or recoving homeostasis of the complex neuroendocrine network during development and aging.

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References

  1. Havrankova, J, Schmechel, D, Roth, J, and Brownstein, M J: Identification of insulin in rat brain. Proc. Natl. Acad. Sci. USA, 75: 5737–5741, 1978.

    PubMed  CAS  Google Scholar 

  2. Havrankova, J, Roth, J, and Brownstein, M J: Insulin receptors are widely distributed in the central nervous system of the rat. Nature, 272: 827–829, 1978.

    Article  PubMed  CAS  Google Scholar 

  3. Young, WS, III, Kuhar, MJ, Roth, J, and Brownstein, MJ: Radiohistochemical localization of insulin receptors in the adult and developing rat brain. Neuropeptides, 1: 15–22, 1980.

    Article  CAS  Google Scholar 

  4. Gammeltoft, S, Staun-Olsen, P, Ottesen, B, and Fahrenkrug, J: Insulin receptors in rat brain cortex. Kinetic evidence for a receptor subtype in the central nervous system. Peptides, 5: 937–944, 1984.

    Article  PubMed  CAS  Google Scholar 

  5. Hill, JM, Lesniak, MA, Pert, CB, and Roth, J: Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience, 17: 1127–1138, 1986.

    Article  PubMed  CAS  Google Scholar 

  6. Barbaccia, M, Chuang, D, and Costa, E: Is insulin a neuromodulator? Adv. Biochem. Psychopharmacol., 33: 511–518, 1982.

    PubMed  CAS  Google Scholar 

  7. Oomura, Y, and Kita, H: Insulin acting as a modulator of feeding through the hypothalamus. Diabetologia, 20(suppl.): 290–298, 1981.

    PubMed  CAS  Google Scholar 

  8. McGowan, MK, Andrews, KM, and Grossman, SP: Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol. Behav., 51(4): 753–766, 1992.

    Article  PubMed  CAS  Google Scholar 

  9. Amir, S, and Shechter, Y: Centrally mediated hypoglycemic effect of insulin apparent involvement of specific insulin receptors. Brain Res., 418(1): 152–156, 1987.

    Article  PubMed  CAS  Google Scholar 

  10. Woods, SC, Chavez, M, Park, CR, Riedy, C, Kaiyala, K, Richardson, RD, Figlewicz, DP, Schwartz, MW, Porte, D, Jr., and Seeley, R J: The evaluation of insulin as a metabolic signal influencing behavior via the brain. Neurosci. Biobehav. Rev., 20: 139–144, 1996.

    Article  PubMed  CAS  Google Scholar 

  11. Raizada, MK, Boyd, FT, Clarke, DW, and Le Roith, D: Physiologically unique insulin receptors on neuronal cells, in Insulin, Insulin-like Growth Factors, and Their Receptors in the Central Nervous System, edited by Raizada, MK, Phillips, MI, and LeRoith, D. New York, Plenum Press, 1987, pp. 191–200.

    Google Scholar 

  12. Zaia, A, and Piantanelli, L: Insulin receptors in the brain: age-related modifications, in Vitality, Mortality and Aging, 5, edited by Viidik, A, and Hofecker, G. Wien, Facultas Universitatsverlag, 1996, pp. 147–158.

    Google Scholar 

  13. Yip, CC, Moule, ML, and Yeung, CW: Characterization of insulin receptor subunits in brain and other tissues by photoaffinity labeling. Biochem. Biophys. Res. Commun., 96: 1671–1678, 1980.

    Article  PubMed  CAS  Google Scholar 

  14. Heidenreich, KA, Zahniser, NR, Berhanu, P, Brandenburg, D, and Olefsky, JM: Structural differences between insulin receptors in the brain and peripheral target tissues. J. Biol. Chem., 258: 8527–8530, 1983.

    PubMed  CAS  Google Scholar 

  15. Lowe, WL, Boyd, FT, Clarke, DW, Raizada, MK, Hart, C, and Le Roith, D: Development of brain insulin receptors: structural and functional studies of insulin receptors from whole brain and primary cell cultures. Endocrinology, 119: 25–35, 1986.

    Article  PubMed  CAS  Google Scholar 

  16. Boyd, FT, Jr., and Raizada, MK: Effects of insulin and tunicamycin on neuronal insulin receptors in culture. Am. J. Physiol., 245: C283–C287, 1983.

    PubMed  CAS  Google Scholar 

  17. Van Schravendijk, CF, Hooghe-Peters, EL, De Meyts, P, and Pipeleers, DG: Identification and characterization of insulin receptors on foetal-mouse brain-cortical cells. Biochem. J., 220: 165–172, 1984.

    PubMed  Google Scholar 

  18. Zahniser, NR, Goens, MB, Hanaway, PJ, and Vinyeh, JV: Characterization and regulation of insulin receptors in rat brain. J. Neurochem., 42: 1353–1362, 1984.

    Google Scholar 

  19. Zaia, A, and Piantanelli, L: Alterations of brain insulin receptor characteristics in aging mice. Arch. Gerontol. Geriatr., 23: 27–37, 1996.

    Article  PubMed  CAS  Google Scholar 

  20. Zaia, A, and Piantanelli, L: Insulin receptors in mouse brain: age-related modifications are corrected by thymus graft. Mech. Ageing Dev., 98: 37–46, 1997.

    Article  PubMed  CAS  Google Scholar 

  21. Basso, A, Piantanelli, L, Rossolini, G, and Roth, GS: Reduced DNA synthesis in primary cultures of hepatocytes from old mice is restored by thymus graft. J. Gerontol., 53A: B111–B116, 1998.

    CAS  Google Scholar 

  22. Piantanelli, L, Basso, A, Muzzioli, M, and Fabris, N: Thymus-dependent reversibility of physiological and Isoproterenol-evoked age-related parameters in athymic (nude) and old normal mice. Mech. Ageing Dev., 7(3): 171–182, 1978.

    Article  PubMed  CAS  Google Scholar 

  23. Fattoretti, P, Viticchi, C, and Piantanelli, L: Age-dependent decrease of beta-adrenoceptor density in the submandibular glands of mice and its modulation by the thymus. Arch. Gerontol. Geriatr., 1: 229–235, 1982.

    Article  PubMed  CAS  Google Scholar 

  24. Piantanelli, L, Gentile, S, Fattoretti, P, and Viticchi, C: Thymic regulation of brain cortex beta-adrenoceptors during development and aging. Arch. Gerontol. Geriatr., 4: 179–185, 1985.

    Article  PubMed  CAS  Google Scholar 

  25. Viticchi, C, Gentile, S, and Piantanelli, L: Aging and thymus-induced differential regulation of beta-1 and beta-2 adrenoceptors of mouse brain cortex. Arch. Gerontol. Geriatr., 8: 13–20, 1989.

    Article  PubMed  CAS  Google Scholar 

  26. Viticchi, C, Rossolini, G, and Piantanelli, L: Age-related Isoproterenol-stimulated adenylyl-cyclase activity are partially corrected by thymic graft. Ann. N.Y. Acad. Sci., 650: 105–108, 1992.

    PubMed  CAS  Google Scholar 

  27. Meneilly, GS, and Hill, A: Alterations in glucose metabolism in patients with Alzheimer’s disease. J. Am. Geriatr. Soc., 41(7): 710–714, 1993.

    PubMed  CAS  Google Scholar 

  28. Craft, S, Gagogo-Jack, SE, Wiethop, BV, Murphy, C, Nevins, RT, Fleischman, S, Rice, V, Newcomer, JW, and Cryer, PE: Effects of hyperglycemia on dence for the presence in calf thymus of a peptidic factor controlling DNA transcription in vitro. Biochim. Biophys. Acta, 414: 9–19, 1975.

    Google Scholar 

  29. Amici, D, Maraldi, N, Marsili, G, Palatroni, P, and Gianfranceschi, GL: Regulatory activity of DNA-binding peptides on some metabolic pathways altered in aging. Mech. Ageing Dev., 23: 215–234, 1983.

    Article  PubMed  CAS  Google Scholar 

  30. Rossolini, G, Basso, A, Piantanelli, L, Tacconi, R, Amici, D, and Gianfranceschi, GL: Neuroendocrine thymus and ?-adrenergic responsiveness in aging mice. Arch. Gerontol. Geriatr., 3: 311–318, 1992.

    CAS  Google Scholar 

  31. Basso, A, Piantanelli, L, Rossolini, G, Amici, D, and Gianfranceschi, GL: Differential influence of a thymic extract on ?-and ?-adrenoceptors of mouse brain cortex. Ann. N.Y. Acad. Sci., 741: 124–128, 1994.

    PubMed  CAS  Google Scholar 

  32. Lowry, OH, Rosebrough, NJ, Farr, AL, and Randall, RJ: Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193: 265–275, 1951.

    PubMed  CAS  Google Scholar 

  33. Roth, RA: Bacitracin: an inhibitor of the insulin degrading activity of glutathione-insulin transhydrogenase. Biochem. Biophys. Res. Commun., 98: 431–438, 1981.

    Article  PubMed  CAS  Google Scholar 

  34. Munson, PJ, and Rodbard, D: Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal. Biochem., 107: 220–239, 1980.

    Article  PubMed  CAS  Google Scholar 

  35. Zaia, A, and Piantanelli, L: Assay of insulin receptors in mouse brain. J. Biol. Res., 3–4-Vol. LXXII: 95–102, 1996.

    Google Scholar 

  36. Kar, S, Chabot, JG, and Quirion, R: Quantitative autoradiographic localization of [125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J. Comp. Neurol., 333: 375–397, 1993.

    Article  PubMed  CAS  Google Scholar 

  37. Garcia-De Lacoba, M, Alarcon, C, De-La Rosa, EJ, and De Pablo, F: Insulin/insulin-like growth factor I hybrid receptors with high affinity for insulin are developmentally regulated during neurogenesis. Endocrinology, 140: 233–243, 1999.

    Article  PubMed  CAS  Google Scholar 

  38. Frolich, L, Blum-Degen, D, Bernstein, HG, Engelsberger, S, Humrich, J, Laufer, S, Muschner, D, Thalheimer, A, Turk, A, Hoyer, S, Zochling, R, Boissl, KW, Jellinger, K, and Riederer, P: Brain insulin and insulin receptors in aging and sporadic Alzheimer’s desease. J. Neural. Tansm., 105: 423–438, 1998.

    Article  CAS  Google Scholar 

  39. Uotani, S, Yamaguchi, Y, Yokota, H, Yamasaki, H, Takino, H, Chikuba, N, Goto, Y, Fujishima, N, Yano, M, Matsumoto, K, et al: Molecular analysis of insulin receptor gene in Werner’s syndrome. Diabetes Res. Clin. Pract., 26: 171–176, 1994.

    Article  PubMed  CAS  Google Scholar 

  40. Izumino, K, Sakamaki, H, Ishibashi, M, Takino, H, Yamasaki, H, Yamaguchi, Y, Chikuba, N, Matsumoto, K, Akazawa, S, Tokuyama, K, and Nagataki, S: Troglitazone ameliorates insulin resistance in patients with Werner’s syndrome. J. Clin. Endocrinol. Metab., 82: 2391–2395, 1997.

    Article  PubMed  CAS  Google Scholar 

  41. Kappy, MS, and Raizada, MK: Adult level insulin binding in term fetal CNS membranes. Brain Res., 249: 390–392, 1982.

    Article  PubMed  CAS  Google Scholar 

  42. Brennan, WA, Jr.: Insulin receptors in brain development, in Insulin, Insulin-like Growth Factors, and Their Receptors in the Central Nervous System, edited by Raizada, MK, Phillips, MI, and LeRoith, D. New York, Plenum Press, 1987, pp. 201–208.

    Google Scholar 

  43. Tchilian, EZ, Zhelezarov, IE, Petkov, VV, and Hdjiivanova, Cl: 125I-insulin binding is decreased in olfactory bulbs of aged rats. Neuropeptides, 17: 193–196, 1990.

    Article  PubMed  CAS  Google Scholar 

  44. Fabris, N, and Piantanelli, L: Thymus, hormones and ageing, in Vth European Symposium on Basic Research in Gerontology, edited by Schmidt, UJ, Bruschke, G, Lang, E, Viidik, A, Platt, D, Frolkis, VV, and Schultz, FH Verlag Dr. med. D. Straube, Erlangen, 1977, pp. 151–166.

    Google Scholar 

  45. Piantanelli, L, and Fabris, N: Hypopituitary dwarf and athymic nude mice and the study of the relationships among thymus hormones and aging, in Genetic Effects on Aging. Birth Defects. Original Article Series, edited by Harrison, DE, New York, A.R. Liss Inc., Vol. XIV n.1, 1978, pp. 315–333.

    Google Scholar 

  46. Fabris, N, Mocchegiani, E, Muzzioli, M, and Provinciali, M: Neuroendocrine-thymus interactions: perspectives for intervention in aging. Ann. N.Y. Acad. Sci., 521: 72–87, 1988.

    PubMed  CAS  Google Scholar 

  47. Comsa, J, Phillip, EM, and Leonhardt, H: Effect of thymectomy on the endocrine glands of the rat. Isr. J. Med. Sci., 13: 354, 1977.

    PubMed  CAS  Google Scholar 

  48. Hall, NR, McGillis, JP, Spangelo, BL, Vahouny, GV, and Goldstein, AL: Modulatory interactions between the central nervous system and immune system, in Thymic Hormones and Lymphokines, Basic Chemistry and Clinical Applications, edited by Goldstein, AL, New York, Plenum Press, 1984, p. 313.

    Google Scholar 

  49. Rebar, RW: Effects of thymic peptides on hypothalamic-pituitary function, in Thymic Hormones and Lymphokines, Basic Chemistry and Clinical Applications, edited by Goldstein, AL, New York, Plenum Press, 1984, pp. 325–334.

    Google Scholar 

  50. Healy, DL, Hall, NR, Schulte, HM, Chrousos, GP, Goldstein, AL, Loriaux, DL, and Hodgen, GD: Pituitary responses to acute administration of thymosin and to thymectomy in prepubertal primates, in Thymic Hormones and Lymphokines, Basic Chemistry and Clinical Applications, edited by Goldstein, AL, New York, Plenum Press, 1984, pp. 365–374.

    Google Scholar 

  51. Dabrowski, MP, and Dabrowska-Bernstein, BK: Thymus and neuro-endocrine-immune regulation of homeostasis, in Immunoregulatory role of thymus, edited by Dabrowski, MP, and Dabrowska-Bernstein, BK USA, CRC Press Inc., 1990, pp. 97–127.

    Google Scholar 

  52. Savino, W, Villa-Verde, DM, Alves, LA, and Dardenne, M: Neuroendocrine control of the thymus. Ann. N.Y. Acad. Sci., 840: 470–479, 1998.

    Article  PubMed  CAS  Google Scholar 

  53. Pieri, C, Giuli, C, Del Moro, M, and Piantanelli, L: Electron-microscopic morphometric analysis of mouse liver. II. Effect of ageing and thymus transplantation in old animals. Mech. Ageing Dev., 13: 275–283, 1980.

    Article  PubMed  CAS  Google Scholar 

  54. Pieri, C, Giuli, C, Bertoni-Freddari, C, Piantanelli, L, and Nagy, IZ: Thymic control on the polyploidization of hepatocytes during aging. Experientia, 38: 680–681, 1982.

    Article  PubMed  CAS  Google Scholar 

  55. Viticchi, C, and Piantanelli, L: Thymus and age modulate the beta-adrenergic mediated adenylate cyclase activity in brain cortex of mice, in Protein Metabolism in Aging, edited by Bergamini, E, New York, Wiley-Liss Inc., 1990, pp. 325–329.

    Google Scholar 

  56. Rossolini, G, Viticchi, C, Basso, A, Zaia, A, and Piantanelli, L: Thymus-induced recovery of age-related decrease of brain cortex α-and β-adrenoceptors. Int. J. Neurosci., 59:143–150, 1991.

    Article  PubMed  CAS  Google Scholar 

  57. Zaia, A, Viticchi, C, and Piantanelli, L: Differential regulation of brain β-adrenoceptor subpopulations in aging rodents. Ann. N.Y. Acad. Sci., 673: 200–205, 1992.

    PubMed  CAS  Google Scholar 

  58. Goya, RG, and Bolognani, F: Homeostasis, thymic hormones and aging. Gerontology, 45: 174–178, 1999.

    Article  PubMed  CAS  Google Scholar 

  59. Sauter, A, Goldstein, M, Engel, J, and Ueta, K: Effect of insulin on central catecholamines. Brain Res., 260: 330–333, 1983.

    Article  PubMed  CAS  Google Scholar 

  60. Boyd, FT, Jr., Clarke, DW, and Raizada, MK: Insulin inhibits specific norepinephrine uptake in neuronal cultures from rat brain. Brain Res., 398: 1–5, 1986.

    Article  PubMed  CAS  Google Scholar 

  61. Richards, EM, Raizada, MK, and Sumners, C: Insulin downregulates alpha-2 adrenergic receptors in cultured glial cells, in Insulin, Insulin-like Growth Factors, and Their Receptors in the Central Nervous System, edited by Raizada, MK, Phillips, MI, and LeRoith, D. New York, Plenum Press, 1987, pp. 209–214.

    Google Scholar 

  62. Figlewicz, DP, and Szot, P: Insulin stimulates membrane phospholipid metabolism by enhancing endogenous a1-adrenergic activity in the rat hyppocampus. Brain Res., 550: 101–107, 1991.

    Article  PubMed  CAS  Google Scholar 

  63. Wilcox, BJ, Matsumoto, AM, Dorsa, DM, and Baskin, DG: Reduction of insulin binding in the arcuate nucleus of the rat brain after 6-hydroxydopamine treatment. Brain Res., 500: 149–155, 1989.

    Article  PubMed  CAS  Google Scholar 

  64. Phillips, MI: Insulin in the brain: a feedback loop involving brain insulin and circumventricular organs, in Insulin, Insulin-like Growth Factors, and Their Receptors in the Central Nervous System, edited by Raizada, MK, Phillips, MI, and LeRoith, D. New York, Plenum Press, 1987, pp. 163–175.

    Google Scholar 

  65. Piantanelli, L, Fattoretti, P, and Viticchi, C: Beta-adrenoceptor changes in submandibular glands of old mice. Mech. Ageing Dev., 14: 155–164, 1980.

    Article  PubMed  CAS  Google Scholar 

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  1. Gerontol. Res. Dept. INRCA, Center of Biochemistry, Via Birarelli, 8, I-60121, Ancona, Italy

    Annamaria Zaia & Lucio Piantanelli

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  1. Annamaria Zaia
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Zaia, A., Piantanelli, L. Insulin receptors in mouse brain: Reversibility of age-related impairments by a thymic extract. AGE 23, 133–139 (2000). https://doi.org/10.1007/s11357-000-0015-8

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