Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Physiology and Biochemistry

Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity

Abstract

Background

Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring.

Methods

Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake.

Results

Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring.

Conclusions

Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Growth trajectory and brain weights of Control and PLP rats.
Fig. 2: Venn diagrams of maternal protein restriction during lactation on ARC gene expression in 3-month-old male offspring according to three different analyses: GCOS, GC-RMA and RMA.
Fig. 3: RT-PCR validation of the differentially expressed genes in the ARC of Control and postnatal low protein (PLP) rats identified with microarray.
Fig. 4: PLP rats are more sensitive to the anorectic effect of d-fenfluramine.
Fig. 5: Enhanced 5-HT-induced food intake in PLP rats is 5-HT5AR-mediated.
Fig. 6: Effect of 5-HT5AR agonist 5-CT combined with NPY on food intake.

References

  1. Bianco-Miotto T, Craig JM, Gasser YP, van Dijk SJ, Ozanne SE. Epigenetics and DOHaD: from basics to birth and beyond. J Dev Orig Health Dis. 2017;8:513–9.

    CAS  PubMed  Google Scholar 

  2. Ozanne SE, Hales CN. Lifespan: catch-up growth and obesity in male mice. Nature. 2004;427:411–2.

    CAS  PubMed  Google Scholar 

  3. Rkhzay-Jaf J, O’Dowd JF, Stocker CJ. Maternal obesity and the fetal origins of the metabolic syndrome. Curr Cardiovasc Risk Rep. 2012;6:487–95.

    PubMed  PubMed Central  Google Scholar 

  4. Jimenez-Chillaron JC, Hernandez-Valencia M, Lightner A, Faucette RR, Reamer C, Przybyla R, et al. Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight. Diabetologia. 2006;49:1974–84.

    CAS  PubMed  Google Scholar 

  5. Remmers F, Fodor M, Delemarre-van de Waal HA. Neonatal food restriction permanently alters rat body dimensions and energy intake. Physiol Behav. 2008;95:208–15.

    CAS  PubMed  Google Scholar 

  6. Stocker CJ, Wargent ET, Martin-Gronert MS, Cripps RL, O’Dowd JF, Zaibi MS, et al. Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y. Int J Obes. 2012;36:1040–6.

    CAS  Google Scholar 

  7. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med. 1976;295:349–53.

    CAS  PubMed  Google Scholar 

  8. Cripps RL, Martin-Gronert MS, Archer ZA, Hales CN, Mercer JG, Ozanne SE. Programming of hypothalamic energy balance gene expression in rats by maternal diet during pregnancy and lactation. Clin Sci. 2009;117:85–93.

    CAS  Google Scholar 

  9. Tungalagsuvd A, Matsuzaki T, Iwasa T, Munkhzaya M, Yiliyasi M, Kawami T, et al. The expression of orexigenic and anorexigenic factors in middle-aged female rats that had been subjected to prenatal undernutrition. Int J Dev Neurosci. 2016;49:1–5.

    CAS  PubMed  Google Scholar 

  10. Wattez JS, Delahaye F, Lukaszewski MA, Risold PY, Eberlé D, Vieau D, et al. Perinatal nutrition programs the hypothalamic melanocortin system in offspring. Horm Metab Res. 2013;45:980–90.

    CAS  PubMed  Google Scholar 

  11. Claycombe KJ, Uthus EO, Roemmich JN, Johnson LK, Johnson WT. Prenatal low-protein and postnatal high-fat diets induce rapid adipose tissue growth by inducing Igf2 expression in Sprague Dawley rat offspring. J Nutr. 2013;143:1533–9.

    CAS  PubMed  Google Scholar 

  12. García AP, Palou M, Sánchez J, Priego T, Palou A, Picó C. Moderate caloric restriction during gestation in rats alters adipose tissue sympathetic innervation and later adiposity in offspring. PLoS ONE. 2011;6:e17313.

    PubMed  PubMed Central  Google Scholar 

  13. Palou M, Priego T, Romero M, Szostaczuk N, Konieczna J, Cabrer C, et al. Moderate calorie restriction during gestation programs offspring for lower BAT thermogenic capacity driven by thyroid and sympathetic signaling. Int J Obes. 2015;39:339–45.

    CAS  Google Scholar 

  14. Glavas MM, Joachim SE, Draper SJ, Smith MS, Grove KL. Melanocortinergic activation by melanotan II inhibits feeding and increases uncoupling protein 1 messenger ribonucleic acid in the developing rat. Endocrinology. 2007;148:3279–87.

    CAS  PubMed  Google Scholar 

  15. Grove KL, Grayson BE, Glavas MM, Xiao XQ, Smith MS. Development of metabolic systems. Physiol Behav. 2005;86:646–60.

    CAS  PubMed  Google Scholar 

  16. Delahaye F, Breton C, Risold PY, Enache M, Dutriez-Casteloot I, Laborie C, et al. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology. 2008;149:470–5.

    CAS  PubMed  Google Scholar 

  17. Muhlhausler BS, Adam CL, Findlay PA, Duffield JA, McMillen IC. Increased maternal nutrition alters development of the appetite-regulating network in the brain. FASEB J. 2006;20:1257–59.

    CAS  PubMed  Google Scholar 

  18. Chen H, Simar D, Lambert K, Mercier J, Morris MJ. Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology. 2008;149:5348–56.

    CAS  PubMed  Google Scholar 

  19. Heisler LK, Lam DD. An appetite for life: brain regulation of hunger and satiety. Curr Opin Pharmacol. 2017;37:100–6.

    CAS  PubMed  Google Scholar 

  20. Paradis J, Boureau P, Moyon T, Nicklaus S, Parnet P, Paillé V. Perinatal western diet consumption leads to profound plasticity and GABAergic phenotype changes within hypothalamus and reward pathway from birth to sexual maturity in rat. Front Endocrinol. 2017;8:216.

    Google Scholar 

  21. Lopes de Souza S, Orozco-Solis R, Grit I, Manhães de Castro R, Bolaños-Jiménez F. Perinatal protein restriction reduces the inhibitory action of serotonin on food intake. Eur J Neurosci. 2008;27:1400–8.

    PubMed  Google Scholar 

  22. Manuel-Apolinar L, Rocha L, Damasio L, Tesoro-Cruz E, Zarate A. Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake. Mol Med Rep. 2014;9:407–12.

    CAS  PubMed  Google Scholar 

  23. Martin-Gronert MS, Stocker CJ, Wargent ET, Cripps RL, Garfield AS, Jovanovic Z, et al. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Dis Model Mech. 2016;9:401–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. D’Agostino G, Lyons D, Cristiano C, Lettieri M, Olarte-Sanchez C, Burke LK, et al. Nucleus of the solitary tract serotonin 5-HT2C receptors modulate food intake. Cell Metab. 2018;28:619–30.

    PubMed  PubMed Central  Google Scholar 

  25. Blundell JE, Lawton CL, Halford JC. Serotonin, eating behaviour, and fat intake. Obes Res. 1995;3 Suppl 4:471S–6S.

    CAS  PubMed  Google Scholar 

  26. Calu DJ, Chen YW, Kawa AB, Nair SG, Shaham Y. The use of the reinstatement model to study relapse to palatable food seeking during dieting. Neuropharmacology. 2014;76:395–406.

    CAS  PubMed  Google Scholar 

  27. Burke LK, Heisler LK. 5-hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol. 2015;27:389–98.

    CAS  PubMed  Google Scholar 

  28. Petry CJ, Ozanne SE, Wang CL, Hales CN. Early protein restriction and obesity independently induce hypertension in 1-year-old rats. Clin Sci. 1997;93:147–52.

    CAS  Google Scholar 

  29. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press: Sydney, Australia; 1998.

  30. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.

    PubMed  Google Scholar 

  31. Wu Z, Irizarry RA, Gentleman R, Martinez-Murillo F, Spencer F. A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc. 2004;99:909–17.

    Google Scholar 

  32. Jourdan D, Piec I, Gaulier JM, Lacassie E, Alliot J. Effect of fenfluramine on caloric intake and macronutrient selection in Lou/c rats during aging. Neurobiol Aging. 2003;24:67–76.

    CAS  PubMed  Google Scholar 

  33. Muñoz-Islas E, Vidal-Cantú GC, Bravo-Hernández M, Cervantes-Durán C, Quiñonez-Bastidas GN, Pineda-Farias JB, et al. Spinal 5-HT5A receptors mediate 5-HT-induced antinociception in several pain models in rats. Pharmacol Biochem Behav. 2014;120:25–32.

    PubMed  Google Scholar 

  34. Nikiforuk A, Hołuj M, Kos T, Popik P. The effects of a 5-HT5A receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia. Neuropharmacology. 2016;105:351–60.

    CAS  PubMed  Google Scholar 

  35. Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P, et al. CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology. 2007;52:279–90.

    CAS  PubMed  Google Scholar 

  36. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.

    Google Scholar 

  37. Motulsky HJ, Brown RE. Detecting outliers when fitting data with nonlinear regression – a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics. 2006;7:123.

    PubMed  PubMed Central  Google Scholar 

  38. Vienberg SG, Kleinridders A, Suzuki R, Kahn CR. Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity. Mol Metab. 2014;4:144–50.

    PubMed  PubMed Central  Google Scholar 

  39. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, et al. Activation of central melanocortin pathways by fenfluramine. Science. 2002;297:609–11.

    CAS  PubMed  Google Scholar 

  40. Gabr M. Malnutrition during pregnancy and lactation. World Rev Nutr Diet. 1981;36:90–9.

    CAS  PubMed  Google Scholar 

  41. Miller M, Hasson R, Morgane PJ, Resnick O. Adrenalectomy: its effects on systemic tryptophan metabolism in normal and protein malnourished rats. Brain Res Bull. 1980;5:451–9.

    CAS  PubMed  Google Scholar 

  42. Resnick O, Morgane PJ, Hasson R, Miller M. Overt and hidden forms of chronic malnutrition in the rat and their relevance to man. Neurosci Biobehav Rev. 1982;6:55–75.

    CAS  PubMed  Google Scholar 

  43. Dearden L, Bouret SG, Ozanne SE. Sex and gender differences in developmental programming of metabolism. Mol Metab. 2018;15:8–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Arch JR, Trayhurn P. Detection of thermogenesis in rodents in response to anti-obesity drugs and genetic modification. Front Physiol. 2013;4:64.

    PubMed  PubMed Central  Google Scholar 

  45. Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014;311:2167–8.

    CAS  PubMed  Google Scholar 

  46. Lam DD, Garfield AS, Marston OJ, Shaw J, Heisler LK. Brain serotonin system in the coordination of food intake and body weight. Pharmacol Biochem Behav. 2010;97:84–91.

    CAS  PubMed  Google Scholar 

  47. Jean A, Laurent L, Bockaert J, Charnay Y, Dusticier N, Nieoullon A, et al. The nucleus accumbens 5-HTR4-CART pathway ties anorexia to hyperactivity. Transl Psychiatry. 2012;11:e203.

    Google Scholar 

  48. Kumar KK, Tung S, Iqbal J. Bone loss in anorexia nervosa: leptin, serotonin, and the sympathetic nervous system. Ann NY Acad Sci. 2010;1211:51–65.

    CAS  PubMed  Google Scholar 

  49. Pratt WE, Blackstone K, Connolly ME, Skelly MJ. Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion. Behav Neurosci. 2009;123:1046–57.

    CAS  PubMed  Google Scholar 

  50. Kassai F, Schlumberger C, Kedves R, Pietraszek M, Jatzke C, Lendvai B, et al. Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression. Behav Pharmacol. 2012;23:397–406.

    CAS  PubMed  Google Scholar 

  51. Zhang Y, Smith EM, Baye TM, Eckert JV, Abraham LJ, Moses EK, et al. Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels. Physiol Genomics. 2010;42:168–176.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Pickens CL, Cifani C, Navarre BM, Eichenbaum H, Theberge FR, Baumann MH, et al. Effect of fenfluramine on reinstatement of food seeking in female and male rats: implications for the predictive validity of the reinstatement model. Psychopharmacology. 2012;221:341–53.

    CAS  PubMed  Google Scholar 

  53. Nelson DL. 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3:53–58.

    CAS  PubMed  Google Scholar 

  54. Chen ZF, Paquette AJ, Anderson DJ. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat Genet. 1998;20:136–42.

    CAS  PubMed  Google Scholar 

  55. Lemonde S, Rogaeva A, Albert PR. Cell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene. J Neurochem. 2004;88:857–68.

    CAS  PubMed  Google Scholar 

  56. Dhariwala FA, Rajadhyaksha MS. An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol. 2008;28:351–69.

    CAS  PubMed  Google Scholar 

  57. Teegarden SL, Scott AN, Bale TL. Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling. Neuroscience. 2009;162:924–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Mashima R, Hishida Y, Tezuka T, Yamanashi Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev. 2009;232:273–85.

    CAS  PubMed  Google Scholar 

  59. Hosooka T, Noguchi T, Kotani K, Nakamura T, Sakaue H, Inoue H, et al. Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. Nat Med. 2008;14:188–93.

    CAS  PubMed  Google Scholar 

  60. Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT. Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem. 2004;279:30369–74.

    CAS  PubMed  Google Scholar 

  61. Rani S, Mehta JP, Barron N, Doolan P, Jeppesen PB, Clynes M, et al. Decreasing Txnip mRNA and protein levels in pancreatic MIN6 cells reduces reactive oxygen species and restores glucose regulated insulin secretion. Cell Physiol Biochem. 2010;25:667–74.

    CAS  PubMed  Google Scholar 

  62. Chutkow WA, Birkenfeld AL, Brown JD, Lee HY, Frederick DW, Yoshioka J, et al. Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity. Diabetes. 2010;59:1424–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Blouet C, Liu SM, Jo YH, Chua S, Schwartz GJ. TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity. J Neurosci. 2012;32:9870–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lappalainen Z, Lappalainen J, Oksala NK, Laaksonen DE, Khanna S, Sen CK, et al. Diabetes impairs exercise training-associated thioredoxin response and glutathione status in rat brain. J Appl Physiol. 2009;106:461–7.

    CAS  PubMed  Google Scholar 

  65. Levendusky MC, Basle J, Chang S, Mandalaywala NV, Voigt JM, Dearborn RE. Jr. Expression and regulation of vitamin D3 upregulated protein 1 (VDUP1) is conserved in mammalian and insect brain. J Comp Neurol. 2009;517:581–600.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Biotechnology and Biological Sciences Research Council (Grant codes BB/E00797X/1, BB/E007821/1, BB/R01857X/1, BB/N017838/1) and Medical Research Council (MC/PC/15077). Microarray hybridization was carried out by Molecular Biology Services at the University of Warwick.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Claire J. Stocker.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wargent, E.T., Martin-Gronert, M.S., Cripps, R.L. et al. Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity. Int J Obes 44, 1946–1957 (2020). https://doi.org/10.1038/s41366-020-0643-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-0643-2

Search

Quick links