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Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation

Abstract

Objective:

To examine the neurobiological basis of bingeing-related eating disorders using an animal model system.

Design:

Sprague–Dawley pups were separated from dam for 3 h daily during the first two weeks of birth (maternal separation (MS)), or left undisturbed (non-handled (NH)). Pups were subjected to repeated fasting/refeeding (RF) cycles; that is, 24 h food deprivation and 24 h RF (NH/RF or MS/RF), or had free access to food and water (NH/fed control (FC) or MS/FC) from postnatal day (PND) 28–40.

Measurements:

Body weight gain and food intake were recorded. The arcuate expression of neuropeptide Y (NPY) and plasma corticosterone levels were analyzed on PND 29 and 40.

Results:

Decrease in weight gain by repeated fasting/RF cycles was smaller in MS pups than in NH. Interestingly, weight changes responding to fasting or RF increased in MS/RF compared with NH/RF. Compensatory hyperphagia was diminished in NH/RF after the third fasting trial, but persisted in MS/RF throughout the experimental period. The arcuate expression of NPY mRNA responding to food deprivation was blunted, but elevation of plasma corticosterone exaggerated, in the MS group, compared to the NH group, on PND 29 after the first fasting session. However, both the arcuate NPY mRNA and plasma corticosterone levels were increased in MS/RF, but not in NH/RF, on PND 40 after the six sets of fasting/RF cycles, compared to the free FC groups.

Conclusion:

Experience of neonatal MS may lead to an exaggerated feeding response to repeated fasting/RF challenges at adolescence, perhaps, due to increased responsiveness of the hypothalamic–pituitary–adrenal gland axis. Additionally, the results suggested that an increased action of the hypothalamic NPY may not be necessary to induce compensatory hyperphagia following food deprivation.

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References

  1. Wonderlich SA, Brewerton TD, Jocic Z, Dansky BS, Abbott DW . The relationship of childhood sexual abuse and eating disorders: a review. J Am Acad Child Adolesc Psychiatry 1997; 36: 1107–1115.

    CAS  PubMed  Google Scholar 

  2. Koo-Loeb JH, Costello N, Light KC, Girdler SS . Women with eating disorder tendencies display altered cardiovascular, neuroendocrine, and physiological profiles. Psychosom Med 2000; 62: 539–548.

    CAS  PubMed  Google Scholar 

  3. Putignano P, Dubini A, Toja P, Invitti C, Bonfanti S, Redaelli G et al. Salivary cortisol measurement in normal-weight, obese and anorexic women: comparison with plasma cortisol. Eur J Endocrinol 2001; 145: 165–171.

    CAS  PubMed  Google Scholar 

  4. Gluck ME, Geliebter A, Lorence M . Cortisol stress response is positively correlated with central obesity in obese women with binge eating disorder (BED) before and after cognitive-behavioral treatment. Ann NY Acad Sci 2004; 1032: 202–207.

    CAS  PubMed  Google Scholar 

  5. Plotsky PM, Meaney MJ . Early, postnatal experience alters hypothalamic corticotrophin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 1993; 18: 195–200.

    CAS  PubMed  Google Scholar 

  6. Suchecki D, Tufik S . Long-term effects of maternal deprivation on the corticosterone response to stress in rats. Am J Physiol 1997; 273: R1332–R1338.

    CAS  PubMed  Google Scholar 

  7. van Oers HJ, de Kloet ER, Levine S . Early vs late maternal deprivation differentially alters the endocrine and hypothalamic responses to stress. Dev Brain Res 1998; 111: 245–252.

    CAS  Google Scholar 

  8. Liu D, Caldji C, Sharma S, Plotsky PM, Meaney MJ . Influence of neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinephrine release in the hypothalamic paraventricular nucleus. J Neuroendocrinol 2000; 12: 5–12.

    PubMed  Google Scholar 

  9. Strack AM, Sebastian RJ, Schwartz MW, Dallman MF . Glucocorticoids and insulin: reciprocal signals for energy balance. Am J Physiol 1995; 268: R142–R149.

    CAS  PubMed  Google Scholar 

  10. Cavagnini F, Croci M, Putignano P, Petroni ML, Invitti C . Glucocorticoids and neuroendocrine function. Int J Obes 2000; 24: S77–S79.

    CAS  Google Scholar 

  11. Tempel DL, Leibowitz SF . Adrenal steroid receptors: interactions with brain neuropeptide systems in relation to nutrient intake and metabolism. J Neuroendocrinol 1994; 6: 479–501.

    CAS  PubMed  Google Scholar 

  12. Zakrzewska KE, Cusin I, Stricker-Krongard A, Boss O, Ricquier D, Jeanrenaud B et al. Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. Diabetes 1999; 48: 365–370.

    CAS  PubMed  Google Scholar 

  13. Jimenez-Vasquez PA, Mathe AA, Thomas JD, Riley EP, Ehlers CL . Early maternal separation alters neuropeptide Y concentrations in selected brain regions in adult rats. Brain Res Dev Brain Res 2001; 131: 149–152.

    CAS  PubMed  Google Scholar 

  14. Husum H, Mathe AA . Early life stress changes concentration of neuropeptide Y and corticotrophin-releasing hormone in adult rat brain. Lithium treatment modifies these changes. Neuropsychopharmacology 2002; 5: 756–764.

    Google Scholar 

  15. Stanley BG, Leibowitz SF . Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 1985; 82: 3940–3943.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS . Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.

    CAS  PubMed  Google Scholar 

  17. Schwartz MW, Woods SC, Porte JD, Seeley RJ, Baskin DG . Central nervous system control of food intake. Nature 2000; 404: 661–671.

    CAS  PubMed  Google Scholar 

  18. White BD, Dean RG, Martin RJ . Adrenalectomy decreases neuropeptide Y mRNA levels in the arcuate nucleus. Brain Res Bull 1990; 25: 711–715.

    CAS  PubMed  Google Scholar 

  19. Cintra A, Fuxe K, Solfrini V, Agnati LF, Tinner B, Wikstrom AC et al. Central peptidergic neurons as targets for glucocorticoid action. Evidence for the presence of glucocorticoid receptor immunoreactivity in various types of classes of peptidergic neurons. J Steroid Biochem Mol Biol 1991; 40: 93–103.

    CAS  PubMed  Google Scholar 

  20. Ponsalle P, Srivastava LS, Uh RM, White JD . Glucocorticoids are required for food deprivation-induced increases in hypothalamic neuropeptide Y expression. J Neuroendocrinol 1992; 4: 585–591.

    CAS  PubMed  Google Scholar 

  21. Makimura H, Mizno TM, Isoda F, Beasley J, Silverstein JH, Mobbs CV . Role of glucocorticoids in mediating effects of fasting and diabetes on hypothalamic gene expression. BMC Physiol 2003; 3: 1–13.

    Google Scholar 

  22. Kim HJ, Lee JH, Choi SH, Lee YS, Jahng JW . Fasting-induced increases of arcuate NPY mRNA and plasma corticosterone are blunted in the rat experienced neonatal maternal separation. Neuropeptides 2005; 39: 587–594.

    CAS  PubMed  Google Scholar 

  23. Lee JH, Kim HJ, Kim JG, Ryu V, Kim BT, Kang DW et al. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neurosci Res 2007; 58: 32–39.

    CAS  PubMed  Google Scholar 

  24. Tauscer J, Pirket W, Willeit M, de Zwaan M, Bailer U, Neumeister A et al. [I-123] beta-CIT and SPECT reveal reduced brain serotonin transporter availability in bulimia nervosa. Biol Psychiatry 2001; 49: 326–332.

    Google Scholar 

  25. Stamatakis EA, Hetherington MM . Neuroimaging in eating disorders. Nutr Neurosci 2003; 6: 325–334.

    PubMed  Google Scholar 

  26. Fairburn CG, Harrison PJ . Eating disorders. Lancet 2003; 361: 407–416.

    PubMed  Google Scholar 

  27. Polivy J . Psychological consequences of food restriction. J Am Diet Assoc 1996; 96: 589–592.

    CAS  PubMed  Google Scholar 

  28. Rorty M, Yager J, Rossotto E . Childhood sexual, physical, and psychological abuse in bulimia nervosa. Am J Psychiatry 1994; 151: 1122–1126.

    CAS  PubMed  Google Scholar 

  29. Grilo CM, Masheb RM . Childhood psychological, physical, and sexual maltreatment in outpatients with binge eating disorder: frequency and associations with gender, obesity, and eating-related psychopathology. Obes Res 2001; 9: 320–325.

    CAS  PubMed  Google Scholar 

  30. Paxinos G, Watson C . The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego, 1986.

    Google Scholar 

  31. Jahng JW, Houpt TA, Kim SJ, Joh TH, Son JH . Neuropeptide Y mRNA and serotonin innervations in the arcuate nucleus of anorexia mutant mice. Brain Res 1998; 790: 67–73.

    CAS  PubMed  Google Scholar 

  32. Choi SH, Kwon BS, Lee S, Houpt TA, Lee HT, Jahng JW . Systemic 5-hydroxy-L-tryptophan down-regulates the arcuate CART mRNA level in rats. Regul Peptides 2003; 115: 73–80.

    CAS  Google Scholar 

  33. Graham B, Chang S, Lin D, Yakubu F, Hill JO . Effect of weight cycling on susceptibility to dietary obesity. Am J Physiol 1990; 259: R1096–R1102.

    CAS  PubMed  Google Scholar 

  34. Stein LJ, Stellar E, West DB, Greenwood MRC, Foster GD, Feurer I et al. Early-onset repeated dieting reduces food intake and body weight but not adiposity in dietary-obese female rats. Physiol Behav 1991; 51: 1–6.

    Google Scholar 

  35. Sea MM, Fong WP, Huang Y, Chen ZY . Weight cycling-induced alteration in fatty acid metabolism. Am J Physiol Regul Integr Comp Physiol 2000; 279: R1145–R1155.

    CAS  PubMed  Google Scholar 

  36. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS . Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci USA 1991; 88: 10931–10935.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Swart I, Jahng JW, Overton JM, Houpt TA . Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice. Am J Physiol Regul Integr Comp Physiol 2002; 283: R1020–R1026.

    CAS  PubMed  Google Scholar 

  38. Bi S, Robinson BM, Moran TH . Acute food deprivation and chronic food restriction differently affect hypothalamic NPY mRNA expression. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1030–R1036.

    CAS  PubMed  Google Scholar 

  39. Sindelar DK, Mystkowski P, Marsh DJ, Palmiter RD, Schwartz MW . Attenuation of diabetic hyperphagia in neuropeptide Y-deficient mice. Diabetes 2002; 51: 778–783.

    CAS  PubMed  Google Scholar 

  40. Namkoong C, Kim MS, Jang PG, Han SM, Park HS, Koh EH et al. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes 2005; 54: 63–68.

    CAS  PubMed  Google Scholar 

  41. Timofeeva E, Picard F, Duclos M, Deshaies Y, Richard D . Neural activation and corticotrophin-releasing hormone expression in the brain of obese (fa/fa) and lean (fa/?) Zucker rats in response to refeeding. Eur J Neurosci 2002; 15: 1013–1029.

    PubMed  Google Scholar 

  42. Kim YM, Lee JY, Choi SH, Kim D, Jahng JW . RU486 blocks fasting-induced decrease of neuronal nitric oxide synthase in the rat paraventricular nucleus. Brain Res 2004; 1018: 221–226.

    CAS  PubMed  Google Scholar 

  43. Jahng JW, Lee JY, Yoo SB, Kim YM, Ryu V, Kang DW et al. Refeeding-induced expression of neuronal nitric oxide synthase in the rat paraventricular nucleus. Brain Res 2005; 1048: 185–192.

    CAS  PubMed  Google Scholar 

  44. Ladd CO, Owens MJ, Nemeroff CB . Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137: 1212–1218.

    CAS  PubMed  Google Scholar 

  45. McIntosh J, Animan H, Merali Z . Short- and long periods of neonatal maternal separation differentially affect anxiety and feeding in adult rats: gender-dependent effects. Brain Res Dev Brain Res 1999; 113: 97–106.

    CAS  PubMed  Google Scholar 

  46. Iwasaki S, Inoue K, Kriike N, Hikiji K . Effect of maternal separation on feeding behavior of rats in later life. Physiol Behav 2000; 70: 551–556.

    CAS  PubMed  Google Scholar 

  47. Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG . Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharm Biochem Behav 2002; 73: 131–140.

    CAS  Google Scholar 

  48. Kochan Z, Goyke E, Karbowska J, Slominska E, Swierczynski J . The decrease of rat postprandial plasma triglycerol concentration after multiple cycles of starvation–refeeding. Horm Metab Res 2001; 33: 26–29.

    CAS  PubMed  Google Scholar 

  49. Kim YW, Scarpace PJ . Repeated fasting/refeeding elevates plasma leptin without increasing fat mass in rats. Physiol Behav 2003; 78: 459–464.

    CAS  PubMed  Google Scholar 

  50. Corwin RL, Buda-Levin A . Behavioral models of binge-type eating. Physiol Behav 2004; 82: 123–130.

    CAS  PubMed  Google Scholar 

  51. Corwin RL, Wojnicki FHE, Fisher JO, Dimitriou SG, Rice HB, Young MA . Limited access to a dietary fat option affects ingestive behavior but not body composition in male rats. Physiol Behav 1998; 65: 545–553.

    CAS  PubMed  Google Scholar 

  52. Marcus MD, Kalarchian MA . Binge eating in children and adolescents. Int J Eat Disord (Suppl) 2003; 34: S47–S57.

    Google Scholar 

  53. Birketvedt GS, Drivenes E, Agledahl I, Sundsfjord J, Olstad R, Florholmen JR . Bulimia nervosa––a primary defect in the hypothalamic–pituitary–adrenal axis? Appetite 2006; 46: 164–167.

    CAS  PubMed  Google Scholar 

  54. Diaz-Marsa M, Carrasco JL, Basurte E, Pastrana JI, Saiz-Ruiz J, Lopez-Ibor JJ . Findings with 0.25 mg dexamethasone suppression test in eating disorders: association with childhood trauma. CNS Spectr 2007; 12: 675–680.

    PubMed  Google Scholar 

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Acknowledgements

We thank Drs ND Geary and TH Moran for helpful comments on this study. This study was supported by Neurobiology Research Program of KMOST & the Korea Research Foundation Grant funded by MOEHRD (KRF-2006-353-E00017) given to JWJ.

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Correspondence to J-H Lee or J W Jahng.

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Ryu, V., Lee, JH., Yoo, S. et al. Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation. Int J Obes 32, 1355–1362 (2008). https://doi.org/10.1038/ijo.2008.108

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