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Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

International Journal of Obesity volume 31, pages 1210–1221 (2007)Cite this article

Abstract

Objective:

Male Sprague–Dawley rats maintained from birth on a high-fat diet were examined to determine whether a specific measure before puberty can identify and allow one to characterize prepubertal rats at normal weight with high vs low risk for adult obesity.

Materials and methods:

Measures from weaning (day 21) to around puberty (day 45) were taken of weight gain, absolute body weight and daily energy intake on a high-fat diet and related to the amount of body fat accumulated at maturity (80–100 days of age). Rats identified by a specific prepubertal measure as obesity-prone (OP) vs obesity-resistant (OR) were then characterized before and after puberty.

Results:

Prepubertal weight gain from days 30 to 35 of age was the strongest and earliest positive correlate of ultimate body fat accrual in adult rats. The highest (8–10 g/day) compared to lowest (5–7 g/day) weight-gain scores identified accurately and reproducibly distinct OP and OR subgroups at day 35 that became obese or remained lean, respectively, as adults. The OP rats with rapid prepubertal weight gain and 50% greater adiposity at maturity (day 100) exhibited the expected phenotype of already-obese rats. These included elevated levels of leptin, insulin, triglycerides and glucose, increased galanin (GAL) peptide levels in the paraventricular nucleus (PVN) and reduced neuropeptide Y (NPY) levels in the arcuate nucleus (ARC). Before puberty (day 35), the OP rats with normal fat pad weights, energy intake and endocrine profile similar to OR rats exhibited these disturbances characteristic of obese rats. They had decreased capacity for fat oxidation in muscle, increased GAL expression in PVN and reduced expression of NPY and agouti-related protein in ARC.

Conclusion:

Prepubertal weight gain can identify OP rats on day 35 when they have minimal body fat but exhibit specific metabolic and neurochemical disturbances expected to promote obesity and characteristics of already-obese adult rats.

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References

  1. Pagliassotti MJ, Knobel SM, Shahrokhi KA, Manzo AM, Hill JO . Time course of adaptation to a high-fat diet in obesity-resistant and obesity-prone rats. Am J Physiol 1994; 267: R659–R664.

    Article  CAS  Google Scholar 

  2. Gayles EC, Pagliassotti MJ, Prach PA, Koppenhafer TA, Hill JO . Contribution of energy intake and tissue enzymatic profile to body weight gain in high-fat-fed rats. Am J Physiol 1997; 272: R188–R194.

    CAS  PubMed  Google Scholar 

  3. Shor-Posner G, Brennan G, Ian C, Jasaitis R, Madhu K, Leibowitz SF . Meal patterns of macronutrient intake in rats with particular dietary preferences. Am J Physiol 1994; 266: R1395–R1402.

    CAS  PubMed  Google Scholar 

  4. Shor-Posner G, Ian C, Brennan G, Cohn T, Moy H, Ning A, Leibowitz SF . Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: characterization of three subpopulations. Physiol Behav 1991; 50: 1187–1195.

    Article  CAS  Google Scholar 

  5. Wang J, Alexander JT, Zheng P, Yu HJ, Dourmashkin J, Leibowitz SF . Behavioral and endocrine traits of obesity-prone and obesity-resistant rats on macronutrient diets. Am J Physiol 1998; 274: E1057–E1066.

    Article  CAS  Google Scholar 

  6. Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE . Selective breeding for diet-induced obesity and resistance in Sprague–Dawley rats. Am J Physiol 1997; 273: R725–R730.

    CAS  PubMed  Google Scholar 

  7. Levin BE . Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats. Am J Physiol 1999; 276: R382–R387.

    CAS  PubMed  Google Scholar 

  8. Dourmashkin JT, Chang GQ, Hill JO, Gayles EC, Fried SK, Leibowitz SF . Model for predicting and phenotyping at normal weight the long-term propensity for obesity in Sprague–Dawley rats. Physiol Behav 2006; 87: 666–678.

    Article  CAS  Google Scholar 

  9. Leibowitz SF, Chang GQ, Dourmashkin JT, Yun R, Julien C, Pamy PP . Leptin secretion after a high-fat meal in normal-weight rats: strong predictor of long-term body fat accrual on a high-fat diet. Am J Physiol Endocrinol Metab 2006; 290: E258–E267.

    Article  CAS  Google Scholar 

  10. Berthoud HR, Bereiter DA, Trimble ER, Siegel EG, Jeanrenaud B . Cephalic phase, reflex insulin secretion. Neuroanatomical and physiological characterization. Diabetologia 1981; 20 (Suppl): 393–401.

    Article  CAS  Google Scholar 

  11. Ji H, Friedman MI . Fasting plasma triglyceride levels and fat oxidation predict dietary obesity in rats. Physiol Behav 2003; 78: 767–772.

    Article  CAS  Google Scholar 

  12. Lauterio TJ, Barkan A, DeAngelo M, DeMott-Friberg R, Ramirez R . Plasma growth hormone secretion is impaired in obesity-prone rats before onset of diet-induced obesity. Am J Physiol 1998; 275: E6–E11.

    CAS  PubMed  Google Scholar 

  13. Pagliassotti MJ, Gayles EC, Hill JO . Fat and energy balance. Ann NY Acad Sci 1997; 827: 431–448.

    Article  CAS  Google Scholar 

  14. Leibowitz SF, Dourmashkin JT, Chang GQ, Hill JO, Gayles EC, Fried SK, Wang J . Acute high-fat diet paradigms link galanin to triglycerides and their transport and metabolism in muscle. Brain Res 2004; 1008: 168–178.

    Article  CAS  Google Scholar 

  15. Wortley KE, Chang GQ, Davydova Z, Leibowitz SF . Peptides that regulate food intake: orexin gene expression is increased during states of hypertriglyceridemia. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1454–R1465.

    Article  CAS  Google Scholar 

  16. Clegg DJ, Benoit SC, Reed JA, Woods SC, Dunn-Meynell A, Levin BE . Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. Am J Physiol Regul Integr Comp Physiol 2005; 288: R981–R986.

    Article  CAS  Google Scholar 

  17. Wang J, Akabayashi A, Dourmashkin J, Yu HJ, Alexander JT, Chae HJ, Leibowitz SF . Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity. Brain Res 1998; 802: 75–88.

    Article  CAS  Google Scholar 

  18. Lauterio TJ, Davies MJ, DeAngelo M, Peyser M, Lee J . Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity. Obes Res 1999; 7: 498–505.

    Article  CAS  Google Scholar 

  19. Astrup A . Dietary composition, substrate balances and body fat in subjects with a predisposition to obesity. Int J Obes Relat Metab Disord 1993; 17 (Suppl 3): S32–S36.

    PubMed  Google Scholar 

  20. McGuire MT, Wing RR, Klem ML, Lang W, Hill JO . What predicts weight regain in a group of successful weight losers? J Consult Clin Psychol 1999; 67: 177–185.

    Article  CAS  Google Scholar 

  21. Astrup A, Buemann B, Christensen NJ, Toubro S . Failure to increase lipid oxidation in response to increasing dietary fat content in formerly obese women. Am J Physiol 1994; 266: E592–E599.

    CAS  PubMed  Google Scholar 

  22. Filozof C, Gonzalez C . Predictors of weight gain: the biological-behavioural debate. Obes Rev 2000; 1: 21–26.

    Article  CAS  Google Scholar 

  23. Harrington ME, Coscina DV . Early weight gain and behavioral responsivity as predictors of dietary obesity in rats. Physiol Behav 1983; 30: 763–770.

    Article  CAS  Google Scholar 

  24. Toschke AM, Beyerlein A, von Kries R . Children at high risk for overweight: a classification and regression trees analysis approach. Obes Res 2005; 13: 1270–1274.

    Article  Google Scholar 

  25. Danielzik S, Pust S, Landsberg B, Muller MJ . First lessons from the Kiel Obesity Prevention Study (KOPS). Int J Obes (Lond) 2005; 29 (Suppl 2): S78–S83.

    Article  Google Scholar 

  26. Plagemann A, Harder T, Kohlhoff R, Rohde W, Dorner G . Overweight and obesity in infants of mothers wtih long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Rel Metab Dis 1997; 21: 451–456.

    Article  CAS  Google Scholar 

  27. Parsons TJ, Power C, Logan S, Summerbell CD . Childhood predictors of adult obesity: a systematic review. Int J Obes Relat Metab Disord 1999; 23 (Suppl 8): S1–S107.

    PubMed  Google Scholar 

  28. Stettler N, Stallings VA, Troxel AB, Zhao J, Schinnar R, Nelson SE, Ziegler EE, Strom BL . Weight gain in the first week of life and overweight in adulthood: a cohort study of European American subjects fed infant formula. Circulation 2005; 111: 1897–1903.

    Article  Google Scholar 

  29. Odeleye OE, de C, Pettitt DJ, Ravussin E . Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997; 46: 1341–1345.

    Article  CAS  Google Scholar 

  30. Savoye M, Dziura J, Castle J, DiPietro L, Tamborlane WV, Caprio S . Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study. Int J Obes Relat Metab Disord 2002; 26: 942–946.

    Article  CAS  Google Scholar 

  31. Byrnes SE, Baur LA, Bermingham M, Brock K, Steinbeck K . Leptin and total cholesterol are predictors of weight gain in pre-pubertal children. Int J Obes Relat Metab Disord 1999; 23: 146–150.

    Article  CAS  Google Scholar 

  32. Maffeis C . Aetiology of overweight and obesity in children and adolescents. Eur J Pediatr 2000; 159 (Suppl 1): S35–S44.

    Article  Google Scholar 

  33. Treuth MS, Butte NF, Sorkin JD . Predictors of body fat gain in nonobese girls with a familial predisposition to obesity. Am J Clin Nutr 2003; 78: 1212–1218.

    Article  CAS  Google Scholar 

  34. Alexander J, Chang GQ, Dourmashkin JT, Leibowitz SF . Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6J mice compared to control strains. Int J Obes (Lond) 2006; 30: 50–59.

    Article  CAS  Google Scholar 

  35. White CL, Ishihara Y, Dotson TL, Hughes DA, Bray GA, York DA . Effect of a beta-3 agonist on food intake in two strains of rats that differ in susceptibility to obesity. Physiol Behav 2004; 82: 489–496.

    Article  CAS  Google Scholar 

  36. Ricci MR, Levin BE . Ontogeny of diet-induced obesity in selectively bred Sprague–Dawley rats. Am J Physiol Regul Integr Comp Physiol 2003; 285: R610–R618.

    Article  Google Scholar 

  37. Levin BE, Dunn-Meynell AA, Ricci MR, Cummings DE . Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. Am J Physiol Endocrinol Metab 2003; 285: E949–E957.

    Article  CAS  Google Scholar 

  38. Levin BE, Dunn-Meynell AA, Banks WA . Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol 2004; 286: R143–R150.

    Article  CAS  Google Scholar 

  39. American Physiology Society . Guiding principles for research involving animals and human beings. Am J Physiol Regul Integr Comp Physiol 2002; 283: R281–R283.

    Article  Google Scholar 

  40. Srere PA, Kosicki GW . The purification of citrate-condensing enzyme. J Biol Chem 1961; 236: 2557–2559.

    CAS  PubMed  Google Scholar 

  41. Pagliassotti MJ, Pan D, Prach P, Koppenhafer T, Storlien L, Hill JO . Tissue oxidative capacity, fuel stores and skeletal muscle fatty acid composition in obesity-prone and obesity-resistant rats. Obes Res 1995; 3: 459–464.

    Article  CAS  Google Scholar 

  42. Paxinos G, Watson C . The Rat Brain in Stereotaxic Coordinates. Academic Press: Sydney, 1986.

    Google Scholar 

  43. Chang GQ, Karatayev O, Davydova Z, Leibowitz SF . Circulating triglycerides impact on orexigenic peptides and neuronal activity in hypothalamus. Endocrinology 2004; 145: 3904–3912.

    Article  CAS  Google Scholar 

  44. Leibowitz SF, Akabayashi A, Wang J . Obesity on a high-fat diet: role of hypothalamic galanin in neurons of the anterior paraventricular nucleus projecting to the median eminence. J Neurosci 1998; 18: 2709–2719.

    Article  CAS  Google Scholar 

  45. Morton GJ, Schwartz MW . The NPY/AgRP neuron and energy homeostasis. Int J Obes Relat Metab Disord 2001; 25 (Suppl 5): S56–S62.

    Article  CAS  Google Scholar 

  46. Leibowitz SF, Wortley KE . Hypothalamic control of energy balance: different peptides, different functions. Peptides 2004; 25: 473–504.

    Article  CAS  Google Scholar 

  47. Dube MG, Kalra SP, Kalra PS . Hypothalamic galanin is up-regulated during hyperphagia and increased body weight gain induced by disruption of signaling in the ventromedial nucleus. Peptides 2000; 21: 519–526.

    Article  CAS  Google Scholar 

  48. Mercer JG, Lawrence CB, Atkinson T . Regulation of galanin gene expression in the hypothalamic paraventricular nucleus of the obese Zucker rat by manipulation of dietary macronutrients. Brain Res Mol Brain Res 1996; 43: 202–208.

    Article  CAS  Google Scholar 

  49. Pedrazzi P, Cattaneo L, Valeriani L, Boschi S, Cocchi D, Zoli M . Hypothalamic neuropeptide Y and galanin in overweight rats fed a cafeteria diet. Peptides 1998; 19: 157–165.

    Article  CAS  Google Scholar 

  50. Levin BE, Dunn-Meynell AA . Dysregulation of arcuate nucleus preproneuropeptide Y mRNA in diet-induced obese rats. Am J Physiol 1997; 272: R1365–R1370.

    Article  CAS  Google Scholar 

  51. Yun R, Dourmashkin JT, Hill JO, Gayles EC, Fried SK, Leibowitz SF . PVN galanin increases fat storage and promotes obesity by causing muscle to utilize carbohydrate more than fat. Peptides 2005; 26: 2265–2273.

    Article  CAS  Google Scholar 

  52. Dourmashkin JT, Chang GQ, Gayles EC, Hill Jofsk, Julien C, Leibowitz SF . Different forms of obesity as a function of diet composition. Int J Obes Relat Metab Disord 2005; 29: 1368–1378.

    Article  CAS  Google Scholar 

  53. Leibowitz SF . Regulation and effects of hypothalamic galanin: relation to dietary fat, alcohol ingestion, circulating lipids and energy homeostasis. Neuropeptides 2005; 39: 327–332.

    Article  CAS  Google Scholar 

  54. Archer ZA, Rayner DV, Mercer JG . Hypothalamic gene expression is altered in underweight but obese juvenile male Sprague–Dawley rats fed a high-energy diet. J Nutr 2004; 134: 1369–1374.

    Article  CAS  Google Scholar 

  55. Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W, Dorner G . Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res 1999; 836: 146–155.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  57. Giraudo SQ, Kotz CM, Grace MK, Levine AS, Billington CJ . Rat hypothalamic NPY mRNA and brown fat uncoupling protein mRNA after high-carbohydrate or high-fat diets. Am J Physiol 1994; 266: R1578–R1583.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by USPHS Grants MH 43422/DA 21518 (SFL) and DK38088 (JOH). We are most grateful to Ms Olga Karatayev and Kate Sepiashvili for their help in the preparation of this manuscript.

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Authors and Affiliations

  1. The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    K L Leibowitz

  2. The Rockefeller University, New York, NY, USA

    G-Q Chang, P S Pamy & S F Leibowitz

  3. Health Sciences Center, University of Colorado, Denver, CO, USA

    J O Hill & E C Gayles

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  1. K L Leibowitz
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Correspondence to S F Leibowitz.

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Leibowitz, K., Chang, GQ., Pamy, P. et al. Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight. Int J Obes 31, 1210–1221 (2007). https://doi.org/10.1038/sj.ijo.0803634

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