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The Combination of Cholecystokinin and Stress Amplifies an Inhibition of Appetite, Gastric Emptying, and an Increase in c-Fos Expression in Neurons of the Hypothalamus and the Medulla Oblongata

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Abstract

Cholecystokinin (CCK) had been the first gastrointestinal hormone known to exert anorexic effects. CCK had been inferred to contribute to the onset of functional dyspepsia (FD) symptoms. To understand the pathophysiology of FD, the roles of stress have to be clarified. In this study, we aimed to clarify the influence of stress on the action of cholecystokinin (CCK) on appetite and gastric emptying. Using rats, stress was simulated by giving restraint stress or intraperitoneal injection of the stress-related peptide hormone urocortin 1 (UCN1). The effects of CCK and restraint stress, alone or in combination, on food intake and gastric motility were examined, and c-Fos expression in the neurons of appetite control network in the central nervous system was assessed by immunohistochemical staining. CCK inhibited food intake and gastric emptying in a dose-dependent manner. Food intake for 1 h was significantly lower with UCN1 (2 nmol/kg) than with the saline control. Restraint stress amplified the suppressive effects of CCK on food intake for 1 h and on gastric emptying. With regard to brain function, the CCK induced c-Fos expression in the neurons of the nucleus tractus solitarius and paraventricular nucleus of the hypothalamus was markedly and significantly amplified by the addition of restraint stress with CCK. The results suggested that stress might amplify the anorexic effects of CCK through activation of the nuclei that comprise the brain neuronal network for satiation; this might play a role in the pathogenesis of the postprandial distress syndromes of functional dyspepsia.

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Abbreviations

CCK:

Cholecystokinin

CNS:

Central nervous system

FD:

Functional dyspepsia

UCN1:

Urocortin 1

CRF:

Corticotropin-releasing factor

NTS:

Nucleus tractus solitarius

PVN:

Paraventricular nucleus

VMH:

Ventromedial hypothalamus

DMH:

Dorsomedial hypothalamus

ARC:

Arcuate nucleus

LH:

Lateral hypothalamus

References

  1. Gibbs J, Young RC, Smith JP (1973) Cholecystokinin decreases food intake in rats. J Comp Physiol Psycol 84:488–495

    Article  CAS  Google Scholar 

  2. Liddle RA, Goldfine ID, Rosen MS et al (1985) Cholecystokin bioactivity in human plasma. J Clin Invest 75:1144–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Valenzuela JE, Defilippi C (1981) Inhibition of gastric emptying in human by secretion, the octapeptide of cholecystokinin, and intraduodenal fat. Gastroenterology 81:898–902

    Article  CAS  PubMed  Google Scholar 

  4. Kobelt P, Paulitsch S, Goebel M, Stegel M et al (2006) Peripheral injection of CCK-8S induces Fos expression in the dorsomedial hypothalamic nucleus in rats. Brain Res 1117:109–117

    Article  CAS  PubMed  Google Scholar 

  5. Pilichiewicz AN, Feltrin KL, Horowitz M et al (2008) Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY. Am J Gastroenterol 103:2613–2623

    Article  CAS  PubMed  Google Scholar 

  6. Chua AS, Dinan TG, Rovati LC et al (1994) Cholecystokinin hyperresponsiveness in dysmotility-type non-ulcer dyspepsia. Ann N Y Acad Sci 713:298–299

    Article  CAS  PubMed  Google Scholar 

  7. Drossman DA (2006) The functional gastrointestinal disorders and the Rome III process. Gastroenterology 130:1377–1390

    Article  PubMed  Google Scholar 

  8. Malagelada JR, Stanghellini V (1985) Manometric evaluation of functional upper gut symptoms. Gastroenterology 88:1223–1231

    Article  CAS  PubMed  Google Scholar 

  9. Stanghellini V, Ghidini C, Maccarini MR et al (1992) Fasting and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia. Gut 33:184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mearin F, Cucala M, Azpiroz F et al (1991) The origin of symptoms on the brain-gut axis in functional dyspepsia. Gastroenterology 101:999–1006

    Article  CAS  PubMed  Google Scholar 

  11. Aro P, Tally NJ, Ronkeinen J et al (2009) Anxiety is associated with uninvestigated functional dyspepsia (Rome III criteria) in Swedish population-based study. Gastroenterology 137:94–100

    Article  PubMed  Google Scholar 

  12. Henningsen P, Zimmermann T, Sattel H (2003) Medically unexplained physical symptoms, anxiety and depression: a meta-analytic review. Psychosom Med 65:528–533

    Article  PubMed  Google Scholar 

  13. Yakabi K, Noguchi M, Ohno S et al (2011) Urocortin 1 reduces food intake and ghrelin secretion via CRF2 receptors. Am J Physiol Endocrinol Metab 301:E72–E82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harada Y, Ro S, Ochiai M et al (2015) Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model. Neurogastroenterol Motil 27:1089–1097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dragunow M, Faull R (1989) The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 29:261–265

    Article  CAS  PubMed  Google Scholar 

  16. Morgan JI, Cohen DR, Hempstead JL et al (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237:192–197

    Article  CAS  PubMed  Google Scholar 

  17. Paxinos G, Watson G (1998) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  18. Gourcerol G, Wang L, Wang YH et al (2007) Urocortins and cholecystokinin-8 act synergistically to increase satiation in lean but not obese mice: involvement of corticotropin-releasing factor receptor-2 pathway. Endocrinology 148:6115–6123

    Article  CAS  PubMed  Google Scholar 

  19. Hayes MR, Covasa M (2005) CCK and 5-HT act synergistically to suppress food intake through simultaneous activation of CCK-1 and 5-HT3 receptors. Peptides 26:2322–2330

    Article  CAS  PubMed  Google Scholar 

  20. Zorrilla EP, Tache Y, Koob GF (2003) Nibling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol Sci 24:421–427

    Article  CAS  PubMed  Google Scholar 

  21. Tache Y, Perdue MH (2004) Role of peripheral CRF signaling pathways in stress-related alterations of gut motility and mucosal function. Neurogastroenterol Motil 16(Suppl 1):137–142

    Article  PubMed  Google Scholar 

  22. Million M, Maillot C, Saunders P et al (2002) Human urocortin II, a new CRF-related peptide, displays selective CRF2-mediated actions of gastric transit in rats. Am J Physiol 282:G34–G40

    Article  CAS  Google Scholar 

  23. Porcher C, Peinnequin A, Pellissier S et al (2006) Endogenous expression and in vitro study of CRF-related peptides and CRF receptors in the rat gastric antrum. Peptides 27:1464–1475

    Article  CAS  PubMed  Google Scholar 

  24. Mercer JG, Lawrence CB, Copeland PA (1992) Corticotropin-releasing factor binding sites undergo axonal transport in the rat vagus nerve. J Endocrinol 4:281–285

    CAS  Google Scholar 

  25. Kissileff HR, Pi-Sunyer FZ, Thorton J et al (1981) C-terminal octapeptide of cholecystokin decreases food intake in man. J Clin Nutr 34:154–160

    Article  CAS  Google Scholar 

  26. Okere B, Xu L, Roubos EW et al (2010) Restraint stress alters the secretory activity of neurons co-expressing urocortin-1, cocaine- and amphetamine-regulated transcript peptide and nesfatin-1 in the mouse Edinger–Westphal nucleus. Brain Res 1317:92–99

    Article  CAS  PubMed  Google Scholar 

  27. Olson BR, Hoffman GE, Sved AF et al (1992) Cholecystokinin induces c-Fos expression in hypothalamic oxytocinergic neuron projecting to the dorsal vagal complex. Brain Res 569:238–248

    Article  CAS  PubMed  Google Scholar 

  28. Day HE, Mcknight AT, Poat JA et al (1994) Evidence that cholecystokinin induces immediate early gene expression in the brainstem, hypothalamus, and amygdala of the rat by a CCKA receptor mechanism. Neuropharmacology 33:719–727

    Article  CAS  PubMed  Google Scholar 

  29. Mönikes H, Lauer G, Arnold R (1997) Peripheral administration of cholecystokinin activates c-Fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rats. Brain Res 770:277–288

    Article  Google Scholar 

  30. Schwartz MW, Woods SC, Porte D Jr et al (2000) Central nervous system control of food intake. Nature 404:661–671

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a fund from Saitama Medical University.

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Correspondence to Koji Yakabi.

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Yamaguchi, N., Hosomi, E., Hori, Y. et al. The Combination of Cholecystokinin and Stress Amplifies an Inhibition of Appetite, Gastric Emptying, and an Increase in c-Fos Expression in Neurons of the Hypothalamus and the Medulla Oblongata. Neurochem Res 45, 2173–2183 (2020). https://doi.org/10.1007/s11064-020-03079-y

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