, Volume 65, Issue 3, pp 675–682 | Cite as

Adrenalectomy impairs vasoactive intestinal peptide-induced changes in food intake and plasma parameters

  • Marcela Cristina Garnica-Siqueira
  • Andressa Bussetti Martins
  • Larissa Rugila dos Stopa
  • Camila Franciele de Souza
  • Dimas Augusto Morozin Zaia
  • Cristiane Mota Leite
  • Cássia Thaïs Bussamra Vieira ZaiaEmail author
  • Ernane Torres UchôaEmail author
Original Article



The aim of this study is to evaluate the effects of adrenalectomy (ADX) and glucocorticoid in the changes induced by intracerebroventricular (ICV) administration of vasoactive intestinal peptide (VIP) on food intake and plasma parameters, as well as VIP receptor subtype 2 (VPAC2) mRNA expression in different hypothalamic nuclei of male rats.


Male Wistar rats (260–280 g) were subjected to ADX or sham surgery, 7 days before the experiments. Half of ADX animals received corticosterone (ADX + CORT) in the drinking water. Animals with 16 h of fasting received ICV microinjection of VIP or saline (0.9% NaCl). After 15 min: (1) animals were fed, and the amount of food ingested was quantified for 120 min; or (2) animals were euthanized and blood was collected for biochemical measurements. Determination of VPAC2 mRNA levels in LHA, ARC, and PVN was performed from animals with microinjection of saline.


VIP treatment promoted the anorexigenic effect, which was not observed in ADX animals. Microinjection of VIP also induced an increase in blood plasma glucose and corticosterone levels, and a reduction in free fatty acid plasma levels, but adrenalectomy abolished these effects. In addition, adrenalectomy reduced mRNA expression of VPAC2 in the lateral hypothalamic area and arcuate nucleus, but not in the paraventricular nucleus.


These results suggest that adrenal glands are required for VIP-induced changes in food intake and plasma parameters, and these responses are associated with reduction in the expression of VPAC2 in the hypothalamus after adrenalectomy.


VIP Glycemia Corticosterone Free fatty acids Arcuate nucleus of the hypothalamus VPAC2 receptor expression 



We would like to thank the financial support of Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Estado do Paraná, Brasil, for the grants (protocol numbers 23275, 8277, and 24732). MCGS thanks Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for PhD fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the local Ethics Commission on the Use of Animals of UEL (protocol number 14371201744).


  1. 1.
    A.J. Harmar, J. Fahrenkrug, I. Gozes, M. Laburthe, V. May, J.R. Pisegna, D. Vaudry, H. Vaudry, J.A. Waschek, S.I. Said, Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1. Br. J. Pharmacol. 166, 4–17 (2012)CrossRefGoogle Scholar
  2. 2.
    E.M. Lutz, S. Mendelson, K. West, R. Mitchell, A.J. Harmar, Molecular characterisation of novel receptors for PACAP and VIP. Biochem. Soc. Trans. 23, 83S (1995)CrossRefGoogle Scholar
  3. 3.
    K.M. Joo, Y.H. Chung, M.K. Kim, R.H. Nam, B.L. Lee, K.H. Lee, C.I. Cha, Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain. J. Comp. Neurol. 476, 388–413 (2004)CrossRefGoogle Scholar
  4. 4.
    W.J. Sheward, E.M. Lutz, A.J. Harmar, The distribution of vasoactive intestinal peptide2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization. Neuroscience 67, 409–418 (1995)CrossRefGoogle Scholar
  5. 5.
    L.M. Gerhold, T.L. Horvath, M.E. Freeman, Vasoactive intestinal peptide fibers innervate neuroendocrine dopaminergic neurons. Brain Res. 919, 48–56 (2001)CrossRefGoogle Scholar
  6. 6.
    D. Vaudry, B.J. Gonzalez, M. Basille, L. Yon, A. Fournier, H. Vaudry, Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol. Rev. 52, 269–324 (2000)Google Scholar
  7. 7.
    T.B. Usdin, T.I. Bonner, E. Mezey, Two receptors for vasoactive intestinal polypeptide with similar and complementary distributions. Endocrinology 135, 2662–2680 (1994)CrossRefGoogle Scholar
  8. 8.
    S. Ghourab, K.E. Beale, N.M. Semjonous, K.A. Simpson, N.M. Martin, M.A. Ghatei, S.R. Bloom, K.L. Smith, Intracerebroventricular administration of vasoactive intestinal peptide inhibits food intake. Regul. Pept. 172, 8–15 (2011)CrossRefGoogle Scholar
  9. 9.
    A.B. Martins, M.C. Garnica-Siqueira, D.A.M. Zaia, C.T.B.V. Zaia, E.T. Uchôa, Oxytocin participates on the effects of vasoactive intestinal peptide on food intake and plasma parameters. Mol. Cell. Biochem. 437, 177–183 (2018)CrossRefGoogle Scholar
  10. 10.
    L.D. Alexander, L.D. Sander, Vasoactive intestinal peptide stimulates ACTH and corticosterone release after injection into the PVN. Regul. Pept. 51, 221–227 (1994)CrossRefGoogle Scholar
  11. 11.
    J. Wang, A. Akabayashi, J. Dourmashkin, H.J. Yu, J.T. Alexander, H.J. Chae, S.F. Leibowitz, Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity. Brain Res. 802, 75–88 (1998)CrossRefGoogle Scholar
  12. 12.
    B.A. Kumar, S.F. Leibowitz, Impact of acute corticosterone administration on feeding and macronutrient self-selection patterns. Am. J. Physiol. 254, R222–R228 (1988)Google Scholar
  13. 13.
    A.M. Strack, R.J. Sebastian, M.W. Schwartz, M.F. Dallman, Glucocorticoids and insulin: reciprocal signals for energy balance. Am. J. Physiol. 268, R142–R149 (1995)Google Scholar
  14. 14.
    E.T. Uchoa, H.A.C. Sabino, S.G. Ruginsk, J. Antunes-Rodrigues, L.L.K. Elias, Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses. J. Appl. Physiol. 106, 596–604 (2009)CrossRefGoogle Scholar
  15. 15.
    A. Akabayashi, C.T.B.V. Zaia, S.M. Gabriel, I. Silva, W.K. Cheung, S.F. Leibowitz, Intracerebroventricular Injection of dibutyryl cyclic adenosine-3’,5’-monophosphate increases hypothalamic levels of neuropeptide Y. Brain Res. 660, 323–328 (1994)CrossRefGoogle Scholar
  16. 16.
    M.F. Dallman, S.F. Akana, L. Jacobson, N. Levin, C.S. Cascio, J. Shinsako, Characterization of corticosterone feedback regulation of ACTH secretion. Ann. N. Y. Acad. Sci. 512, 402–414 (1987)CrossRefGoogle Scholar
  17. 17.
    M. Aronsson, K. Fuxe, Y. Dong, L.F. Agnati, S. Okret, J.A. Gustafsson, Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization. Proc. Natl Acad. Sci. USA 85, 9331–9335 (1988)CrossRefGoogle Scholar
  18. 18.
    S. Ceccatelli, M. Eriksson, T. Hökfelt, Distribution and coexistence of corticotropin-releasing factor-, neurotensin-, enkephalin-, cholecystokinin-, galanin- and vasoactive intestinal polypeptide/peptide histidine isoleucine-like peptides in the parvocellular part of the paraventricular nucleus. Neuroendocrinology 49, 309–323 (1989)CrossRefGoogle Scholar
  19. 19.
    P.M. Jones, D.J. O’Halloran, M.A. Ghatei, J. Domin, S.R. Bloom, The influence of adrenal hormone status on neuroendocrine peptides in the rat anterior pituitary gland. J. Endocrinol. 127, 437–444 (1990)CrossRefGoogle Scholar
  20. 20.
    K.S.L. Lam, G. Srivastava, S.P. Tam, Divergent effects of glucocorticoid on the gene expression of vasoactive intestinal peptide in the rat cerebral cortex and pituitary. Neuroendocrinology 56, 32–37 (1992)CrossRefGoogle Scholar
  21. 21.
    R. Guillemin, G.W. Clayton, H.S. Lipscomb, J.D. Smith, Fluorometric measurement of rat plasma and adrenal corticosterone concentration. A note on technical details. J. Lab. Clin. Med. 53, 830–832 (1959)Google Scholar
  22. 22.
    G. Paxinos, C. Watson., The Rat Brain in Stereotaxic Coordinates. (Academic Press, San Diego, 2009)Google Scholar
  23. 23.
    K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real- time quantitative PCR and the 2−ΔΔCt method. Methods 25, 402–408 (2001)CrossRefGoogle Scholar
  24. 24.
    T. Tachibana, S. Tomonaga, D. Oikawa, S. Saito, T. Takagi, E.S. Saito, T. Boswell, M. Furuse, Pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide inhibit feeding in the chick brain by different mechanisms. Neurosci. Lett. 348, 25–28 (2003)CrossRefGoogle Scholar
  25. 25.
    P. Trinder, Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J. Clin. Pathol. 22, 158–161 (1969)CrossRefGoogle Scholar
  26. 26.
    K. Falholt, B. Lund, W. Falholt, An easy colorimetric micromethod for routine determination of free fatty acids in plasma. Clin. Chim. Acta 46, 105–111 (1973)CrossRefGoogle Scholar
  27. 27.
    E.T. Uchoa, L.E.C.M. da Silva, M. de Castro, J. Antunes-Rodrigues, L.L.K. Elias, Corticotrophin-releasing factor mediates hypophagia after adrenalectomy, increasing meal-related satiety responses. Horm. Behav. 58, 714–719 (2010)CrossRefGoogle Scholar
  28. 28.
    S.I. Khan, M.A. Cline, T. Aramaki, H. Ueda, T. Tachibana, Feeding response following central administration of chicken vasoactive intestinal peptide in chicks. Gen. Comp. Endocrinol. 184, 61–66 (2013)CrossRefGoogle Scholar
  29. 29.
    M.C. Garnica-Siqueira, A.B. Martins, D.A.M. Zaia, C.M. Leite, E.T. Uchôa, C.T.B.V. Zaia, Corticotrophin-releasing factor mediates vasoactive intestinal peptide-induced hypophagia and changes in plasma parameters. Horm. Behav. 105, 138–145 (2018)CrossRefGoogle Scholar
  30. 30.
    S.S. Almeida, L.H. Duntas, L. Dye, M.L. Nunes, C. Prasad, J.B.T. Rocha, P. Wainwright, C.T.B.V. Zaia, R.C.A. Guedes, Nutrition and brain function: a multidisciplinary virtual symposium. Nutr. Neurosci. 5, 311–320 (2002)CrossRefGoogle Scholar
  31. 31.
    K. Matsuda, K. Maruyama, T. Nakamachi, T. Miura, M. Uchiyama, S. Shioda, Inhibitory effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) on food intake in the goldfish, Carassius auratus. Peptides 26, 1611–1616 (2005)CrossRefGoogle Scholar
  32. 32.
    H.S. Beyer, S.G. Matta, B.M. Sharp, Regulation of the messenger ribonucleic acid for corticotropin-releasing factor in the paraventricular nucleus and other brain sites of the rat. Endocrinology 123, 2117–2123 (1988)CrossRefGoogle Scholar
  33. 33.
    E.T. Uchoa, L.E.C.M. Silva, M. de Castro, J. Antunes-Rodrigues, L.L.K. Elias, Hypothalamic oxytocin neurons modulate hypophagic effect induced by adrenalectomy. Horm. Behav. 56, 532–538 (2009)CrossRefGoogle Scholar
  34. 34.
    E.T. Uchoa, L.E.C.M. Silva, M. de Castro, J. Antunes-Rodrigues, L.L.K. Elias, Glucocorticoids are required for meal-induced changes in the expression of hypothalamic neuropeptides. Neuropeptides 46, 119–124 (2012)CrossRefGoogle Scholar
  35. 35.
    L.D. Alexander, L.D. Sander, Involvement of vasopressin and corticotropin-releasing hormone in VIP- and PHI-induced secretion of ACTH and corticosterone. Neuropeptides 28, 167–173 (1995)CrossRefGoogle Scholar
  36. 36.
    E. Savontaus, I.M. Conwell, S.L. Wardlaw, Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats. Brain Res. 958, 130–138 (2002)CrossRefGoogle Scholar
  37. 37.
    N. Nagai, H. Kajikawa, T. Sasaki, K. Nagai, H. Nakagawa, Hyperglycemic response to intracranial injection of vasoactive intestinal peptide. J. Clin. Biochem. Nutr. 17, 29–34 (1994)CrossRefGoogle Scholar
  38. 38.
    T. Kuo, A. Mcqueen, T.-C. Chen, J.-C. Wang, Regulation of glucose homeostasis by glucocorticoids. Adv. Exp. Med. Biol. 872, 99–126 (2015)CrossRefGoogle Scholar
  39. 39.
    A. Kawai, N. Kuzuya, On the role of glucocorticoid in glucose-induced insulin secretion. Horm. Metab. Res. 9, 361–365 (1977)CrossRefGoogle Scholar
  40. 40.
    M. Kadekaro, M. Ito, P.M. Gross, Local cerebral glucose utilization is increased in acutely adrenaletomized rats. Neuroendocrinology 47, 329–334 (1988)CrossRefGoogle Scholar
  41. 41.
    N. Paquot, P. Schneiter, E. Jéquier, L. Tappy, Effects of glucocorticoids and sympathomimetic agents on basal and insulin-stimulated glucose metabolism. Clin. Physiol. 15, 231–240 (1995)CrossRefGoogle Scholar
  42. 42.
    R.J. Ho, H.C. Meng, The extracortical action of adrenocorticotrophic hormone on the elevation of plasma free fatty acids. Metabolism 13, 361–364 (1964)CrossRefGoogle Scholar
  43. 43.
    M.T. Kibenge, C.B. Chan, Interactions between effects of adrenalectomy and diet on insulin secretion in fa/fa Zucker rats. Can. J. Physiol. Pharmacol. 79, 1–7 (2001)CrossRefGoogle Scholar
  44. 44.
    M.R. Freedman, T.W. Castonguay, J.S. Stern, Effect of adrenalectomy and corticosterone replacement on meal patterns of Zucker rats. Am. J. Physiol. 249, R584–R594 (1985)Google Scholar
  45. 45.
    W. Oelkers, Adrenal insufficiency. N. Engl. J. Med. 335, 1206–1212 (1996)CrossRefGoogle Scholar
  46. 46.
    A.M. Ebeid, R.R. Attia, P. Sundaram, J.E. Fischer, Release of vasoactive intestinal peptide in the central nervous system in man. Am. J. Surg. 137, 123–127 (1979)CrossRefGoogle Scholar
  47. 47.
    J. Miskowiak, B. Andersen, F. Stadil, J. Fahrenkrug, Meal stimulated levels of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) in gastroplasty for morbid obesity. Regul. Pept. 12, 231–236 (1985)CrossRefGoogle Scholar
  48. 48.
    J.M. Kellum, J.F. Kuemmerle, T.M. O’Dorisio, P. Rayford, D. Martin, K. Engle, L. Wolf, H.J. Sugerman, Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann. Surg. 211, 763–770 (1990)CrossRefGoogle Scholar
  49. 49.
    R.F. Harty, P.H. Pearson, T.E. Solomon, J.E. McGuigan, Cholecystokinin, vasoactive intestinal peptide and peptide histidine methionine responses to feeding in anorexia nervosa. Regul. Pept. 36, 141–150 (1991)CrossRefGoogle Scholar
  50. 50.
    I. Dawidson, M. Blom, T. Lundeberg, E. Theodorsson, B. Angmar-Månsson, Neuropeptides in the saliva of healthy subjects. Life Sci. 60, 269–278 (1997)CrossRefGoogle Scholar
  51. 51.
    C.A. Burdon, P. Ruell, N. Johnson, P. Chapman, S. O’Brien, H.T. O’Connor, The effect of ice-slushy consumption on plasma vasoactive intestinal peptide during prolonged exercise in the heat. J. Therm. Biol. 47, 59–62 (2015)CrossRefGoogle Scholar
  52. 52.
    D. Vaudry, A. Falluel-morel, S. Bourgault, M. Basille, D. Burel, O. Wurtz, A. Fournier, B.K.C. Chow, H. Hashimoto, L. Galas, H. Vaudry, Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev. 61, 283–357 (2009)CrossRefGoogle Scholar
  53. 53.
    A. Sarrieau, M. Najimi, F. Chigr, N. Kopp, D. Jordan, W. Rostene, Localization and developmental pattern of vasoactive intestinal polypeptide binding sites in the human hypothalamus. Sinapse 17, 129–140 (1994)CrossRefGoogle Scholar
  54. 54.
    Y. Masuo, T. Ohtaki, Y. Masuda, M. Tsuda, M. Fujino, Binding sites for pituitary adenyloate cyclase activating polypeptide (PACAP) commparison with vasoactive intestinal polypeptide (VIP) binding site localization in rat brain sections. Brain Res. 575, 113–123 (1992)CrossRefGoogle Scholar
  55. 55.
    L. Mounien, P. Bizet, I. Boutelet, G. Gourcerol, A. Fournier, H. Vaudry, S. Jégou, Pituitary adenylate cyclase-activating polypeptide directly modulates the activity of proopiomelanocortin neurons in the rat arcuate nucleus. Neuroscience 143, 155–163 (2006)CrossRefGoogle Scholar
  56. 56.
    L. Mounien, P. Bizet, I. Boutelet, G. Gourcerol, M. Basille, B. Gonzalez, H. Vaudry, S. Jégou, Expression of PACAP receptor mRNAs by neuropeptide Y neurons in the rat arcuate nucleus. Ann. N. Y. Acad. Sci. 1070, 457–461 (2006)CrossRefGoogle Scholar
  57. 57.
    P. Wiik, Glucocorticoids upregulate the high affinity receptors for vasoactive intestinal peptide (VIP) on human mononuclear leucocytes in vitro. Regul. Pept. 35, 19–30 (1991)CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Marcela Cristina Garnica-Siqueira
    • 1
  • Andressa Bussetti Martins
    • 1
  • Larissa Rugila dos Stopa
    • 1
  • Camila Franciele de Souza
    • 1
  • Dimas Augusto Morozin Zaia
    • 2
  • Cristiane Mota Leite
    • 3
  • Cássia Thaïs Bussamra Vieira Zaia
    • 1
    Email author
  • Ernane Torres Uchôa
    • 1
    Email author
  1. 1.Laboratory of Neuroendocrine Physiology and Metabolism, Department of Physiological SciencesState University of LondrinaLondrinaBrazil
  2. 2.Department of Chemistry, Laboratory of Prebiotic ChemistryState University of LondrinaLondrinaBrazil
  3. 3.Universidade Norte do ParanáLondrinaBrazil

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