Skip to main content

Effects of streptozotocin-induced diabetes mellitus and insulin treatment on neuropeptide Y mRNA in the rat hypothalamus

Summary

Levels of neuropeptide Y and neuropeptide Y mRNA are increased in the arcuate nucleus of severely diabetic rats which may be the result of the associated marked hypoinsulinaemia. We hypothesised that if neuropeptide Y mRNA is regulated by physiological changes in circulating insulin, then the relatively minor changes in circulating insulin found in mild diabetes would also affect neuropeptide Y expression and its response to changing insulin levels should be rapid. Neuropeptide Y mRNA was quantified by in situ hybridisation through the rostral, mid and caudal levels of the arcuate nucleus of adult female rats. Neuropeptide Y mRNA was significantly increased at all three levels of the arcuate nucleus, 7 days after i.v. administration of 40 mg/kg streptozotocin. Neuropeptide Y mRNA was not further increased in the arcuate nucleus of animals given 50 mg/kg streptozotocin. In the former group, serum glucose was increased but insulin levels and body weights were the same as in control rats. In the 50 mg/kg streptozotocin group, serum glucose was further increased while serum insulin and body weight were reduced. In addition, neuropeptide Y mRNA was not altered in the hypothalamic dorsomedial nucleus or the thalamic reticular nucleus. When diabetic rats were treated for 20h with s.c. insulin, there was decreased neuropeptide Y mRNA in the arcuate nucleus. We conclude that neuropeptide Y mRNA in the arcuate nucleus is responsive to small changes in circulating insulin levels and the response occurs within 20 h. These data support that circulating insulin may contribute to control of neuropeptide Y expression under physiological conditions.

References

  1. Tatemoto K, Carlquist M, Mutt V (1982) Neuropeptide Y—a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296:659–660

    PubMed  Article  CAS  Google Scholar 

  2. Allen YS, Adrian TE, Allen JM et al. (1983) Neuropeptide Y distribution in the rat brain. Science 221:877–879

    PubMed  Article  CAS  Google Scholar 

  3. Clark JT, Kalra PS, Crowley WR, Kalra SP (1984) Neuropeptide Y and human pancreatic polypeptide stimulate feeding behaviour in rats. Endocrinology 115:427–429

    PubMed  CAS  Google Scholar 

  4. Stanley BG, Leibowitz SF (1984) Neuropeptide Y; stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci 35:2635–2642

    PubMed  Article  CAS  Google Scholar 

  5. McDonald JK, Lumpkin MD, Samson WK, McCann SM (1985) Neuropeptide Y affects secretion of luteinizing hormone and growth hormone in ovariectomized rats. Proc Natl Acad Sci USA 82:561–564

    PubMed  Article  CAS  Google Scholar 

  6. Chronwall BM, Dimaggio DA, Massari VJ, Pickel VM, Ruggiero DA, O'Donohue TL (1985) The anatomy of neuropeptide-Y-containing neurons in the rat brain. Neurosci 15:1159–1181

    Article  CAS  Google Scholar 

  7. Sawchenko PE, Swanson LW, Grzanna R et al. (1985) Colocalization of neuropeptide Y immunoactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. J Comp Neurol 241:138–153

    PubMed  Article  CAS  Google Scholar 

  8. Sahu A, Kalra PS, Kalra SP (1988) Food deprivation and ingestion induces reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides 9:83–86

    PubMed  Article  CAS  Google Scholar 

  9. Beck B, Jhanwar-Uniyal M, Burlet A, Chapleur-Chateau M, Leibowitz SF, Burlet C (1990) Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status. Brain Res 528:245–249

    PubMed  Article  CAS  Google Scholar 

  10. Brady LS, Smith MA, Gold PW, Herkenham M (1990) Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology 52:441–447

    PubMed  CAS  Google Scholar 

  11. White JD, Kershaw M (1990) Increased hypothalamic neuropeptide Y expression following food deprivation. Mol Cell Neurosci 1:41–48

    Article  CAS  Google Scholar 

  12. Marks JL, Li M, Schwartz M, Porte D Jr, Baskin DG (1992) Effect of fasting on regional levels of neuropeptide Y mRNA and insulin receptors in the rat hypothalamus. An autoradiographic study. Mol Cell Neurosci 3:199–205

    Article  CAS  Google Scholar 

  13. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS (1991) Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci USA 88:10931–10935

    PubMed  Article  CAS  Google Scholar 

  14. Williams G, Gill JS, Lee YC, Carduso HM, Okpere BE, Bloom SR (1989) Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozotocin-induced diabetic rats. Diabetes 38:321–327

    PubMed  Article  CAS  Google Scholar 

  15. Sahu A, Sninsky SA, Kalra PS, Kalra SP (1990) Neuropeptide Y concentration in microdissected hypothalamic regions and in vitro release from the medial basal hypothalamic-preoptic area of streptozotocin-diabetic rats with and without insulin substitution therapy. Endocrinology 126:192–198

    PubMed  CAS  Google Scholar 

  16. Abe M, Saito M, Ikeda H, Shimazu T (1991) Increased neuropeptide Y content in the arcuato-paraventricular hypothalamic neuronal system, in both insulin-dependent and non-insulin-dependent diabetic rats. Brain Res 539:223–227

    PubMed  Article  CAS  Google Scholar 

  17. White JD, Olchovsky D, Kershaw M, Berelowitz M (1990) Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acid in streptozotocin-diabetic rats. Endocrinology 126:765–772

    PubMed  CAS  Google Scholar 

  18. Chua SC, Brown AW, Kim J, Hennesy KL, Leibel RL, Hirsch J (1991) Food deprivation and hypothalamic neuropeptide gene expression: effects of strain background and the diabetes mutation. Mol Brain Res 11: 291–299

    PubMed  Article  CAS  Google Scholar 

  19. Schwartz MW, Marks JL, Sipols A et al. (1991) Insulin lowers hypothalamic neuropeptide Y(NPY) mRNA expression in fasted lean but not obese Zucker rats. Endocrinology 128:1645–1648

    Google Scholar 

  20. Schwartz MW, Sipols AJ, Marks JL et al. (1992) Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 130:3608–3616

    PubMed  Article  CAS  Google Scholar 

  21. Felig P (1981) The endocrine pancreas: diabetes mellitus: In: Felig P, Baxter JD, Broadus AE, Frohman LA (eds) Endocrinology and metabolism. 1st edn. McGraw-Hill, New York, pp 761–869

    Google Scholar 

  22. Steffens AB (1970) Plasma insulin content in relation to blood glucose level and meal pattern in the normal and hypothalamic hyperphagic rat. Physiol Behav 5:147–151

    PubMed  Article  CAS  Google Scholar 

  23. Paxinos G, Watson C (1986) The rat brain in steriotaxic coordinates. 2nd edn. Academic Press, San Diego

    Google Scholar 

  24. Marks JL, Eastman CJ (1989) The effect of starvation on insulin binding in rat brain. Neurosci 30:551–556

    Article  CAS  Google Scholar 

  25. Nishimura H, Kuzuya H, Okamoto M et al. (1989) Postreceptor defect in insulin action in streptozotocin-induced diabetic rats. Am J Physiol 256:E624-E630

    PubMed  CAS  Google Scholar 

  26. Dall'Aglio E, Chang H, Hollenbeck CB, Mondon CE, Sims C, Reaven GM (1985) In vivo and in vitro resistance to maximal stimulated glucose disposal in insulin deficiency. Am J Physiol 249:E312-E316

    PubMed  Google Scholar 

  27. Kahn SE, McCulloch, DK, Schwartz MW, Palmer JP, Porte D Jr (1992) Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus. J Clin Endocrin Metab 74:192–197

    Article  CAS  Google Scholar 

  28. Dean RG, White BD (1990) Neuropeptide Y expression in rat brain: effects of adrenalectomy. Neurosci Lett 114:339–344

    PubMed  Article  CAS  Google Scholar 

  29. Crowley WR, Tessel RE, O'Donohue TL, Adler BA, Kalra SP (1985) Effects of ovarian hormones on the concentration of neuropeptide Y in discrete brain regions of the female rat: correlation with serum LH and median eminence LHRH. Endocrinology 117:1151–1157

    PubMed  CAS  Google Scholar 

  30. Streamson CC, Leibel RL, Hirsch J (1991) Food deprivation and age modulate neuropeptide gene expression in the murine hypothalamus and adrenal gland. Mol Brain Res 9:95–101

    Article  Google Scholar 

  31. Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP, Baskin DG (1986) Localization of125I-insulin binding in the rat hypothalamus by quantitative autoradiography. Neurosci Lett 70:17–22

    PubMed  Article  CAS  Google Scholar 

  32. Marks JL, Porte D Jr, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127:3234–3237

    PubMed  CAS  Article  Google Scholar 

  33. van Houten M, Posner BI, Kopriwa BM, Brawer JR (1979) Insulin-binding sites in the rat brain: in vitro localization to the circumventricular organs by quantitative radioautography. Endocrinology 105:666–673

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Marks, J.L., Waite, K. & Li, M. Effects of streptozotocin-induced diabetes mellitus and insulin treatment on neuropeptide Y mRNA in the rat hypothalamus. Diabetologia 36, 497–502 (1993). https://doi.org/10.1007/BF02743264

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02743264

Key words

  • Neuropeptide Y
  • diabetes mellitus
  • insulin action
  • hypothalamus
  • neuropeptides