Skip to main content
SpringerLink
Log in

Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 μg/μl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Aguilera G (2011) HPA axis responsiveness to stress: implications for healthy aging. Exp Gerontol 46:90–95

    Article  CAS  PubMed  Google Scholar 

  • Arase K, York DA, Shimizu H, Shargill N, Bray GA (1988) Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am J Phys 255:E255–E259

    CAS  Google Scholar 

  • Balaskó M, Rostás I, Füredi N, Mikó A, Tenk J, Cseplő P, Koncsecskó-Gáspár M, Soós S, Székely M, Pétervári E (2013) Age and nutritional state influence the effects of cholecystokinin on energy balance. Exp Gerontol 48:1180–1188

    Article  PubMed  Google Scholar 

  • Bao AM, Swaab DF (2007) Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic paraventricular nucleus and the role of sex hormones. Neuroendocrinology 85:27–36

    Article  CAS  PubMed  Google Scholar 

  • Bittencourt JC, Sawchenko PE (2000) Do centrally administered neuropeptides access cognate receptors?: an analysis in the central corticotropin-releasing factor system. J Neurosci 20:1142–1156

    CAS  PubMed  Google Scholar 

  • Brown MR, Fisher LA, Rivier J, Spiess J, Rivier C, Vale W (1982) Corticotropin-releasing factor: effects on the sympathetic nervous system and oxygen consumption. Life Sci 30:207–210

    Article  CAS  PubMed  Google Scholar 

  • Butler PJ (1993) To what extent can heart rate be used as an indicator of metabolic rate in free-living marine mammals. Symp Zool Soc Lond 66:317–332

    Google Scholar 

  • Buwalda B, de Boer SF, Van Kalkeren AA, Koolhaas JM (1997) Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat. Psychoneuroendocrinology 22:297–309

    Article  CAS  PubMed  Google Scholar 

  • Carlin KM, Vale WW, Bale TL (2006) Vital functions of corticotropin-releasing factor (CRF) pathways in maintenance and regulation of energy homeostasis. Proc Natl Acad Sci U S A 103:3462–3467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceccatelli S, Calza L, Giardino L (1996) Age-related changes in the expression of corticotropin-releasing hormone receptor mRNA in the rat pituitary. Brain Res Mol Brain Res 37:175–180

    Article  CAS  PubMed  Google Scholar 

  • Chatzaki E, Murphy BJ, Wang L, Million M, Ohning GV, Crowe PD, Petroski R, Taché Y, Grigoriadis DE (2004) Differential profile of CRF receptor distribution in the rat stomach and duodenum assessed by newly developed CRF receptor antibodies. J Neurochem 88(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Cizza G, Calogero AE, Brady LS, Bagdy G, Bergamini E, Blackman MR, Chrousos GP, Gold PW (1994) Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis withadvancing age. Endocrinology 134:1611–1620

    CAS  PubMed  Google Scholar 

  • Cullen MJ, Ling N, Foster AC, Pelleymounter MA (2001) Urocortin, corticotropin releasing factor-2 receptors and energy balance. Endocrinology 142:992–999

    Article  CAS  PubMed  Google Scholar 

  • Di Francesco V, Fantin F, Omizzolo F, Residori L, Bissoli L, Bosello O, Zamboni M (2007) The anorexia of aging. Dig Dis 25:129–137

    Article  PubMed  Google Scholar 

  • Figueiredo MJ, Fabricio AS, Machado RR, Melo MC, Soares DM, Souza GE (2010) Increase of core temperature induced by corticotropin-releasing factor and urocortin: a comparative study. Regul Pept 165(2–3):191–199

    Article  CAS  PubMed  Google Scholar 

  • Füredi N, Mikó A, Aubrecht B, Gaszner B, Feller D, Rostás I, Tenk J, Soós S, Balaskó M, Balogh A, Pap M, Pétervári E (2016) Regulatory alterations of energy homeostasis in spontaneously hypertensive rats (SHR). J Mol Neurosci 59(4):521–530

    Article  PubMed  Google Scholar 

  • Hotta M, Shibasaki T, Arai K, Demura H (1999) Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats. Brain Res 823:221–225

    Article  CAS  PubMed  Google Scholar 

  • Jura M, Kozak LP (2016) Obesity and related consequences to ageing. Age (Dordr) 38(1):23

    Article  Google Scholar 

  • Justice NJ, Yuan ZF, Sawchenko PE, Vale W (2008) Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 511:479–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kasckow JW, Regmi A, Mulchahey JJ, Plotsky PM, Hauger RL (1999) Changes in brain corticotropin-releasing factor messenger RNA expression in aged Fischer 344 rats. Brain Res 822:228–230

    Article  CAS  PubMed  Google Scholar 

  • Kayali AG, Young VR, Goodman MN (1987) Sensitivity of myofibrillar proteins to glucocorticoid-induced muscle proteolysis. Am J Phys 252:E621–E626

    CAS  Google Scholar 

  • Kawashima S, Sakihara S, Kageyama K, Nigawara T, Suda T (2008) Corticotropin-releasing factor (CRF) is involved in the acute anorexic effect of alpha-melanocyte-stimulating hormone: a study using CRF-deficient mice. Peptides 29(12):2169–2174

    Article  CAS  PubMed  Google Scholar 

  • Kormos V, Gaszner B (2013) Role of neuropeptides in anxiety, stress, and depression: from animals to humans. Neuropeptides 47(6):401–419

    Article  CAS  PubMed  Google Scholar 

  • LeFeuvre RA, Rothwell NJ, Stock MJ (1987) Activation of brown fat thermogenesis in response to central injection of corticotropin releasing hormone in the rat. Neuropharmacology 26:1217–1221

    Article  CAS  PubMed  Google Scholar 

  • Liaw CW, Grigoriadis DE, Lorang MT, De Souza EB, Maki RA (1997) Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors. Mol Endocrinol 11:2048–2053

    Article  CAS  PubMed  Google Scholar 

  • Loenneke JP, Loprinzi PD (2016) Obesity is associated with insulin resistance but not skeletal muscle dysfunction or all-cause mortality. Age (Dordr) 38(1):2

    Article  Google Scholar 

  • Lu XY, Barsh GS, Akil H, Watson SJ (2003) Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci 23:7863–7872

    CAS  PubMed  Google Scholar 

  • Lukkes JL, Staub DR, Dietrich A, Truitt W, Neufeld-Cohen A, Chen A, Johnson PL, Shekhar A, Lowry CA (2011) Topographical distribution of corticotropin-releasing factor type 2 receptor-like immunoreactivity in the rat dorsal raphe nucleus: co-localization with tryptophan hydroxylase. Neuroscience 183:47–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Millward DJ, Garlick PJ, Nnanyelugo DO, Waterlow JC (1976) The relative importance of muscle protein synthesis and breakdown in the regulation of muscle mass. Biochem J 156:185–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morin SM, Ling N, Liu XJ, Kahl SD, Gehlert DR (1999) Differential distribution of urocortin- and corticotropin-releasing factor-like immunoreactivities in the rat brain. Neuroscience 92:281–291

    Article  CAS  PubMed  Google Scholar 

  • Morley JE (2001) Decreased food intake with aging. J Gerontol Med Sci 56:81–88

    Article  Google Scholar 

  • Muglia L, Jacobson L, Dikkes P, Majzoub JA (1995) Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 373:427–432

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, New York

    Google Scholar 

  • Perrin MH, Vale WW (1999) Corticotropin releasing factor receptors and their ligand family. Ann N Y Acad Sci 885:312–328

    Article  CAS  PubMed  Google Scholar 

  • Pétervári E, Garami A, Soós S, Székely M, Balaskó M (2010) Age-dependence of alpha-MSH-induced anorexia. Neuropeptides 44:315–322

    Article  PubMed  Google Scholar 

  • Pétervári E, Szabad AO, Soós S, Garami A, Székely M, Balaskó M (2011a) Central alpha-MSH infusion in rats: disparate anorexic vs. metabolic changes with aging. Regul Pept 166:105–111

    Article  PubMed  Google Scholar 

  • Pétervári E, Soós S, Székely M, Balaskó M (2011b) Alterations in the peptidergic regulation of energy balance in the course of aging. Curr Protein Pept Sci 12:316–324

    Article  PubMed  Google Scholar 

  • Pétervári E, Rostás I, Soós S, Tenk J, Mikó A, Füredi N, Székely M, Balaskó M (2014) Age versus nutritional state in the development of central leptin resistance. Peptides 56:59–67

    Article  PubMed  Google Scholar 

  • Pibiri M, Sulas P, Leoni VP, Perra A, Kowalik MA, Cordella A, Saggese P, Nassa G, Ravo M (2015) Global gene expression profile of normal and regenerating liver in young and old mice. Age (Dordr) 37(3):9796

    Article  Google Scholar 

  • Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K, Sawchenko PE, Vale W (1994) Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. Proc Natl Acad Sci U S A 91:8777–8781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebuffat P, Belloni AS, Rocco S, Andreis PG, Neri G, Malendowicz LK, Gottardo G, Mazzocchi G, Nussdorfer GG (1992) The effects of ageing on the morphology and function of the zonae fasciculata and reticularis of the rat adrenal cortex. Cell Tissue Res 270:265–272

    Article  CAS  PubMed  Google Scholar 

  • Reul JM, Holsboer F (2002) On the role of corticotropin-releasing hormone receptors in anxiety and depression. Dialogues Clin Neurosci 4:31–46

    PubMed  PubMed Central  Google Scholar 

  • Rivest S, Deshaies Y, Richard D (1989) Effects of corticotropin-releasing factor on energy balance in rats are sex dependent. Am J Physiol Regul Integr Comp Physiol 257:R1417–R1422

    CAS  Google Scholar 

  • Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305:325–327

    Article  CAS  PubMed  Google Scholar 

  • Rohner-Jeanrenaud F, Walker CD, Greco-Perotto R, Jeanrenaud B (1989) Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats. Endocrinology 124:733–739

    Article  CAS  PubMed  Google Scholar 

  • Rostás I, Füredi N, Tenk J, Mikó A, Solymár M, Soós S, Székely M, Pétervári E, Balaskó M (2015) Age-related alterations in the central thermoregulatory responsiveness to alpha-MSH. J Therm Biol 49-50:9–15

    Article  PubMed  Google Scholar 

  • Rothwell NJ (1990) Central effects of CRF on metabolism and energy balance. Neurosci Biobehav Rev 14:263–271

    Article  CAS  PubMed  Google Scholar 

  • Sahu A, Kalra PS, Crowley WR, Kalra SP (1988) Evidence that hypothalamic neuropeptide Y secretion decreases in aged male rats: implications for reproductive aging. Endocrinology 122:2199–2203

    Article  CAS  PubMed  Google Scholar 

  • Scaccianoce S, Di Sciullo A, Angelucci L (1990) Age-related changes in hypothalamo-pituitary-adrenocortical axis activity in the rat. In vitro studies Neuroendocrinology 52:150–155

    Article  CAS  PubMed  Google Scholar 

  • Scarpace PJ, Matheny M, Shek EW (2000) Impaired leptin signal transduction with age-related obesity. Neuropharmacology 39:1872–1879

    Article  CAS  PubMed  Google Scholar 

  • Sertié RA, Caminhotto Rde O, Andreotti S, Campaña AB, de Proença AR, de Castro NC, Lima FB (2015) Metabolic adaptations in the adipose tissue that underlie the body fat mass gain in middle-aged rats. Age (Dordr) 37(5):87

    Article  Google Scholar 

  • Sivasinprasasn S, Sa-Nguanmoo P, Pratchayasakul W, Kumfu S, Chattipakorn SC, Chattipakorn N (2015) Obese-insulin resistance accelerates and aggravates cardiometabolic disorders and cardiac mitochondrial dysfunction in estrogen-deprived female rats. Age (Dordr) 37(2):28

    Article  Google Scholar 

  • Soós S, Balaskó M, Jech-Mihálffy A, Székely M, Pétervári E (2010) Anorexic vs. metabolic effects of central leptin infusion in rats of various ages and nutritional states. J Mol Neurosci 41:97–104

    Article  PubMed  Google Scholar 

  • Stengel A, Taché Y (2014) CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Front Neurosci 8:52

  • Tachibana T, Oikawa D, Takahashi H, Boswell T, Furuse M (2007) The anorexic effect of alpha-melanocyte-stimulating hormone is mediated by corticotrophin-releasing factor in chicks. Comp Biochem Physiol A Mol Integr Physiol 147(1):173–178

    Article  PubMed  Google Scholar 

  • Tay L, Ding YY, Leung BP, Ismail NH, Yeo A, Yew S, Tay KS, Tan CH, Chong MS (2015) Sex-specific differences in risk factors for sarcopenia amongst community-dwelling older adults. Age (Dordr) 37(6):121

    Article  CAS  Google Scholar 

  • Tizabi Y, Aguilera G, Gilad GM (1992) Age-related reduction in pituitary corticotropin-releasing hormone receptors in two rat strains. Neurobiol Aging 13:227–230

    Article  CAS  PubMed  Google Scholar 

  • Valassi E, Scacchi M, Cavagnini F (2008) Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis 18:158–168

    Article  CAS  PubMed  Google Scholar 

  • Vale W, Spiess J, River C, River J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta- endorphin. Science 213:1394–1397

    Article  CAS  PubMed  Google Scholar 

  • Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:191–212

    Article  CAS  PubMed  Google Scholar 

  • Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S et al (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:287–292

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Goebel-Stengel M, Stengel A, Wu SV, Ohning G, Taché Y (2011) Comparison of CRF-immunoreactive neurons distribution in mouse and rat brains and selective induction of Fos in rat hypothalamic CRF neurons by abdominal surgery. Brain Res 1415:34–46

  • Wasserman D, Wasserman J, Sokolowski M (2010) Genetics of HPA-axis, depression and suicidality. Eur Psychiatry 25:278–280

    Article  CAS  PubMed  Google Scholar 

  • Williams KW, Scott MM, Elmquist JK (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in adispersed neuronal network. Eur J Pharmacol 660:2–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wysokiński A, Sobów T, Kłoszewska I, Kostka T (2015) Mechanisms of the anorexia of aging-a review. Age (Dordr) 37(4):9821

    Google Scholar 

  • Zambrano E, Reyes-Castro LA, Nathanielsz PW (2015) Aging, glucocorticoids and developmental programming. Age (Dordr) 37(3):9774

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pécs, Hungary.

The authors are grateful for the expert and excellent technical assistance of Ms. M. Koncsecskó-Gáspár, Ms. A. Mihálffy-Jech, Ms. A. Bóka-Kiss, and Ms. E. Sós.

Financial support: MMVBT2013-BM (Hungarian Society for Microcirculation and Vascular Biology), 34039/KA-OTKA/13-02 (University of Pécs), 34039/KA-OTKA/13-25 (University of Pécs), and PTE-AOK-KA-2015-14 (University of Pécs). This research was also supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Program’

Author information

Authors and Affiliations

  1. Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti str, Pécs, H-7624, Hungary

    Judit Tenk, Ildikó Rostás, Nóra Füredi, Alexandra Mikó, Margit Solymár, Szilvia Soós, Miklós Székely, Erika Pétervári & Márta Balaskó

  2. Department of Anatomy, Medical School, University of Pécs, 12 Szigeti str, Pécs, H-7624, Hungary

    Balázs Gaszner

  3. Department of Pharmaceutical Biotechnology, Medical School, University of Pecs, 12 Szigeti str, Pécs, H-7624, Hungary

    Diana Feller

Authors
  1. Judit Tenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ildikó Rostás
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nóra Füredi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandra Mikó
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Margit Solymár
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Szilvia Soós
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Balázs Gaszner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diana Feller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Miklós Székely
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Erika Pétervári
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Márta Balaskó
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Márta Balaskó.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tenk, J., Rostás, I., Füredi, N. et al. Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia. GeroScience 39, 61–72 (2017). https://doi.org/10.1007/s11357-017-9962-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-017-9962-1

Keywords

Search

Navigation