Skip to main content
SpringerLink
Log in

Programmed Alterations in Hypothalamic Neuronal Orexigenic Responses to Ghrelin Following Gestational Nutrient Restriction

  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Intrauterine growth restricted (IUGR) offspring exhibit increased appetite and a propensity to adult obesity. Although the rate of newborn catch-up growth may determine the programming of adult obesity, there is little understanding of mechanisms by which orexigenic pathways are modified. Ghrelin is an orexigenic peptide that acts in the hypothalamic arcuate (ARC) and ventromedial (VMH) nuclei. To examine potential programming effects of IUGR, ghrelin’s actions on ARC and VMH neurons were studied in brain slices of adult offspring previously subjected to maternal food restriction (FR) during pregnancy (FR/AdLib [ad libitum]) and both pregnancy and lactation (FR/FR). FR/FR offspring demonstrated increased baseline neuronal firing frequency in both ARC and VMH when compared with both FR/AdLib and control offspring. Among FR/AdLib pups that exhibit hyperphagia and obesity, ghrelin excited more and inhibited fewerARC neurons when compared with either FR/FR or controls. These results provide evidence of programming of orexigenic/anorexigenic mechanisms depending on the nutrient levels during pregnancy and newbor periods.

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

Similar content being viewed by others

References

  1. Wynne K, Stanley S, McGowan B, Bloom S. Appetite control. J Endocrinol. 2005;184:291–318.

    Article  CAS  PubMed  Google Scholar 

  2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660.

    Article  CAS  PubMed  Google Scholar 

  3. Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37:649–661.

    Article  CAS  PubMed  Google Scholar 

  4. Guan XM, Yu H, Palyha OC, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res. 1997;48:23–29.

    Article  CAS  PubMed  Google Scholar 

  5. Katayama M, Nogami H, Nishiyama J, Kawase T, Kawamura K. Developmentally and regionally regulated expression of growth hormone secretagogue receptor mRNA in rat brain and pituitary gland. Neuroendocrinology. 2000;72:333–340.

    Article  CAS  PubMed  Google Scholar 

  6. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans.J Clin Endocrinol Metab. 2001;86:5992.

    Article  CAS  PubMed  Google Scholar 

  7. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194–198.

    Article  CAS  PubMed  Google Scholar 

  8. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908–913.

    Article  CAS  PubMed  Google Scholar 

  9. Wren AM, Small CJ, Ward HL, et al.The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 2000;141:4325–4328.

    Article  CAS  PubMed  Google Scholar 

  10. Riediger T, Traebert M, Schmid HA, Scheel C, Lutz TA, Scharrer E. Site-specific effects of ghrelin on the neuronal activity in the hypothalamic arcuate nucleus. Neurosci Lett. 2003;341:151–155.

    Article  CAS  PubMed  Google Scholar 

  11. Barker DJ. In utero programming of chronic disease. Clin Sci (Lond). 1998;95:115–128.

    Article  CAS  Google Scholar 

  12. Barker DJ. Intrauterine programming of adult disease. Mol Med Today. 1995;1:418–423.

    Article  CAS  PubMed  Google Scholar 

  13. Phillips DI, Barker DJ, Osmond C. Infant feeding, fetal growth and adult thyroid function. Acta Endocrinol (Copenh). 1993;129:134–138.

    Article  CAS  Google Scholar 

  14. Dodic M, May CN, Wintour EM, Coghlan JP. An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci (Lond). 1998;94:149–155.

    Article  CAS  Google Scholar 

  15. Levin BE, Govek E. Gestational obesity accentuates obesity in obesity-prone progeny. Am J Physiol. 1998;275(4, pt 2): R1374–R1379.

    CAS  PubMed  Google Scholar 

  16. Jones AP, Assimon SA, Friedman MI. The effect of diet on food intake and adiposity in rats made obese by gestational undernutrition. Physiol Behav. 1986;37:381–386.

    Article  CAS  PubMed  Google Scholar 

  17. Faust IM, Johnson PR, Hirsch J. Long-term effects of early nutritional experience on the development of obesity in the rat. J Nutr. 1980;110:2027–2034.

    Article  CAS  PubMed  Google Scholar 

  18. Gillman MW, Rifas-Shiman SL, Camargo CA Jr, et al. Risk of overweight among adolescents who were breastfed as infants. JAMA. 2001;285:2461–2467.

    Article  CAS  PubMed  Google Scholar 

  19. Anguita RM, Sigulem DM, Sawaya AL. Intrauterine food restriction is associated with obesity in young rats. J Nutr. 1993;123:1421–1428.

    CAS  PubMed  Google Scholar 

  20. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000;279:E83–E87.

    Article  CAS  PubMed  Google Scholar 

  21. Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005;288:R91–R96.

    Article  CAS  PubMed  Google Scholar 

  22. Jones AP, Friedman MI. Obesity and adipocyte abnormalities in offspring of rats undernourished during pregnancy. Science. 1982;215:1518–1519.

    Article  CAS  PubMed  Google Scholar 

  23. Jones AP, Simson EL, Friedman MI. Gestational undernutrition and the development of obesity in rats. J Nutr. 1984; 114:1484–1492.

    CAS  PubMed  Google Scholar 

  24. Desai M, Gayle DA, Babu J, Ross MG. Carbohydrate and lipid abnormalities in adult offspring of intrauterine growth restricted (IUGR) newborns [Abstract 91]. J Soc Gynecol Invest. 2005;12(suppl):114A.

    Article  CAS  Google Scholar 

  25. Desai M, Gayle DA, Babu J, Day L, Behare S, Ross MG. High fat, western diets exacerbate programmed obesity in intrauterine growth restricted (IUGR) newborns [Abstract 92]. J Soc Gynecol Invest. 2005;12(suppl):114A.

    Article  CAS  Google Scholar 

  26. Desai M, Gayle DA, Babu J, Day L, Ross MG. Developmental programming of hypercholesterolemia in the absence of obesity [Abstract 795]. J Soc Gynecol Invest. 2005;12(suppl):337A.

    Article  CAS  Google Scholar 

  27. Desai M, Runic R, Nguyen T, Ross MG. Resistance to anorexogenic agent leptin in intrauterine growth restricted offspring. Reprod Sci. 2007;14(suppl):92A.

    Article  Google Scholar 

  28. Liu QS, Han S, Jia YS, Ju G. Selective modulation of excitatory transmission by mu-opioid receptor activation in rat supraoptic neurons. J Neurophysiol. 1999;82:3000–3005.

    Article  CAS  PubMed  Google Scholar 

  29. Shimono K, Brucher F, Granger R, Lynch G, Taketani M. Origins and distribution of cholinergically induced beta rhythms in hippocampal slices.J Neurosci. 2000;20:8462–8473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Swanson L. Brain Maps: Structure of the Rat Brain. 3rd ed. San Diego, CA: Academic Press; 2003.

    Google Scholar 

  31. Kumarnsit E, Johnstone LE, Leng G. Actions of neuropeptide Y and growth hormone secretagogues in the arcuate nucleus and ventromedial hypothalamic nucleus. Eur J Neurosci. 2003;17:937–944.

    Article  PubMed  Google Scholar 

  32. Shimizu N, Oomura Y, Plata-Salaman CR, Morimoto M. Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus. Brain Res. 1987;416:153–156.

    Article  CAS  PubMed  Google Scholar 

  33. Perkins MN, Rothwell NJ, Stock MJ, Stone TW. Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature. 1981;289:401–402.

    Article  CAS  PubMed  Google Scholar 

  34. Fuchs SA, Edinger HM, Siegel A. The organization of the hypothalamic pathways mediating affective defense behavior in the cat. Brain Res. 1985;330:77–92.

    Article  CAS  PubMed  Google Scholar 

  35. Blache D, Fabre-Nys CJ, Venier G. Ventromedial hypothalamus as a target for oestradiol action on proceptivity, receptivity and luteinizing hormone surge of the ewe. Brain Res. 1991;546:241–249.

    Article  CAS  PubMed  Google Scholar 

  36. Chateau D, Plas-Roser S, Aron C. Follicular growth, ovulatory phenomena and ventromedial nucleus lesions in the rat. Endokrinologie. 1981;77:257–268.

    CAS  PubMed  Google Scholar 

  37. Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science. 2004;304:63–64.

    Article  CAS  PubMed  Google Scholar 

  38. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptideY-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology. 1997;66:393–408.

    Article  CAS  PubMed  Google Scholar 

  39. Chen X, Ge YL, Jiang ZY, Liu CQ, Depoortere I, Peeters TL. Effects of ghrelin on hypothalamic glucose responding neurons in rats. Brain Res. 2005;1055:131–136.

    Article  CAS  PubMed  Google Scholar 

  40. Willesen MG, Kristensen P, Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology. 1999;70: 306–316.

    Article  CAS  PubMed  Google Scholar 

  41. Traebert M, Riediger T, Whitebread S, Scharrer E, Schmid HA. Ghrelin acts on leptin-responsive neurones in the rat arcuate nucleus. J Neuroendocrinol. 2002;14:580–586.

    Article  CAS  PubMed  Google Scholar 

  42. van den TM, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. 2004;7:493–494.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, 1000 W. Carson St, Box 3, Torrance, California, 90502, USA

    Yousheng Jia PhD, Tri Nguyen BS, Mina Desai PhD & Michael G. Ross MD, MPH

Authors
  1. Yousheng Jia PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tri Nguyen BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mina Desai PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael G. Ross MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael G. Ross MD, MPH.

Additional information

This work was supported by grants from the National Institutes of Health and the March of Dimes (MGR).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jia, Y., Nguyen, T., Desai, M. et al. Programmed Alterations in Hypothalamic Neuronal Orexigenic Responses to Ghrelin Following Gestational Nutrient Restriction. Reprod. Sci. 15, 702–709 (2008). https://doi.org/10.1177/1933719108316982

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719108316982

Key words

Search

Navigation