Bone Structure and Strength are Enhanced in Rats Programmed by Early Overfeeding

Abstract

Childhood obesity is growing in prevalence. Obesity and bone dysfunctions may be related disorders, and therefore our aim was to study the impact of the early overfeeding (EO) in offspring bone health since weaning up to adulthood. To induce EO during lactation, litter size was adjusted to 3 male rats per litter (SL). Litter containing 10 pups per mother was the control (NL). Bone tissue was evaluated by dual-energy X-ray absorptiometry, computed tomography, microcomputed tomography, biomechanical tests, and serum analyses. SL offspring presented higher body weight, fat mass, lean mass from 21 up to 180 days, hyperphagia, and higher visceral fat mass. Bone analysis showed that SL offspring presented higher total bone mineral density (BMD) only at 180 days, and higher total bone mineral content and higher bone area from 21 until 180 days. At 180 days, SL offspring presented higher femur BMD and fourth lumbar vertebra (LV4) BMD, higher femoral head radiodensity and LV4 vertebral body radiodensity, lower trabecular pattern factor and trabecular separation, however with higher trabecular number, higher maximal load, resilience, stiffness and break load, and lower break deformation. SL group had, at 180 days, higher osteocalcin and lower C-terminal cross-linked telopeptide of type I collagen (CTX I). We have shown that the excess of fat mass contributed to an increased bone mass, and hypothesized that this increase could be mediated by the hypothyroidism and previous higher thyroid hormone action and hyperleptinemia at weaning. Furthermore, the increased biomechanical loading due to increased body weight probably help us to understand the protective effects obesity exerts upon bone health.

Key words

early overfeeding - bone - programming

• References

• 1 Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone?. Nat Clin Pract Rheumatol 2006; 2: 35-43
• 2 Chinn S, Rona RR. Prevalence and trends in overweight and obesity in three cross-sectional studies of British children 1974–94. BMJ 2001; 322: 24-26
• 3 de Onis M, Blössner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010; 92: 1257-1264
• 4 Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998; 101: E5
• 5 Krassas GE, Tzotzas T. Do obese children become obese adults: childhood predictors of adult disease. Pediatr Endocrinol Rev 2004; 3: 455-459
• 6 Dörner G, Hagen N, Witthuhn W. Early postnatal overfeeding as an etiopathogenetic factor in adult obesity. Acta Biol Med Ger 1976; 35: 799-803
• 7 Rodrigues AL, de Moura EG, Passos MC, Dutra SC, Lisboa PC. Postnatal early overnutrition changes the leptin signaling pathway in the hypothalamic-pituitary-thyroid axis of young and adult rats. J Physiol 2009; 587: 2647-2661
• 8 Rodrigues AL, de Moura EG, Passos MC, Trevenzoli IH, da Conceição EP, Bonono IT, Neto JF, Lisboa PC. Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats. J Nutr Biochem 2011; 22: 109-117
• 9 Barker DJ. The developmental origins of adult disease. J Am Coll Nutr 2003; 23: 588S-595S
• 10 Moura EG, Passos MC. Neonatal programming of body weight regulation and energetic metabolism. Biosci Rep 2005; 25: 251-269
• 11 de Moura EG, Lisboa PC, Passos MC. Neonatal programming of neuroimmunomodulation – role of adipocytokines and neuropeptides. Neuroimmunomodulation 2008; 15: 176a-188a
• 12 Jones G. Early life nutrition and bone development in children. Nestle Nutr Workshop Ser Pediatr Program 2011; 68: 227-233
• 13 Devlin MJ, Grasemann C, Cloutier AM, Louis L, Alm C, Palmert MR, Bouxsein ML. Maternal perinatal diet induces developmental programming of bone architecture. J Endocrinol 2013; 217: 69-81
• 14 NIH . Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement 2000; 17: 1-45
• 15 Eastell R, Lambert H. Diet and healthy bones. Calcif Tissue Int 2002; 70: 400-404
• 16 Plagemann A, Heidrich I, Götz F, Rohde W, Dörner G. Obesity and enhanced diabetes and cardiovascular risk in adult rats due to early postnatal overfeeding. Exp Clin Endocrinol 1992; 99: 154-158
• 17 Davidowa H, Plagemann A. Hypothalamic neurons of postnatally overfed, overweight rats respond differentially to corticotropin-releasing hormones. Neurosci Lett 2004; 371: 64-68
• 18 Boullu-Ciocca S, Dutour A, Guillaume V, Achard V, Oliver C, Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. Diabetes 2005; 54: 197-203
• 19 Conceição EP, Moura EG, Trevenzoli IH, Peixoto-Silva N, Pinheiro CR, Younes-Rapozo V, Oliveira E, Lisboa PC. Neonatal overfeeding causes higher adrenal catecholamine content and basal secretion and liver dysfunction in adult rats. Eur J Nutr 2013; 52: 1393-1404
• 20 Conceição EP, Franco JG, Oliveira E, Resende AC, Amaral TA, Peixoto-Silva N, Passos MC, Moura EG, Lisboa PC. Oxidative stress programming in a rat model of postnatal early overnutrition – role of insulin resistance. J Nutr Biochem 2013; 24: 81-87
• 21 Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000; 92: 73-78
• 22 Thrailkill KM, Lumpkin Jr. CK, Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 2005; 289: E735-E745
• 23 Marques RG, Morales MM, Petroianu A. Brazilian law for scientific use of animals. Acta Cir Bras 2009; 24: 69-74
• 24 Lukaski HC, Hall CB, Marchello MJ, Sider WA. Validation of dual x-ray absorptiometry for body-composition assessment of rats exposed to dietary stressors. Nutrition 2001; 17: 607-613
• 25 Sirois I, Cheung AM, Ward WE. Biomechanical bone strength and bone mass in young male and female rats fed a fish oil diet. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 415-442
• 26 Feldkamp LA, Davis LC, Kress JW. Practical cone beam algorithm. J Opt Soc Am A 1984; 1: 612-619
• 27 Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations in three-dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner Res 2000; 15: 32-40
• 28 Trebacz H, Zduneck A. Three-point bending and acoustic emission study of adult rat femora after immobilization and free remobilization. J Biomech 2006; 39: 237-245
• 29 Haarbo J, Gotfredsen A, Hassager C, Christiansen C. Validation of body composition by dual energy X-ray absorptiometry (DEXA). Clin Physiol 1991; 11: 331-341
• 30 Lac G, Cavalie H, Ebal E, Michaux O. Effects of a high fat diet on bone of growing rats Correlations between visceral fat, adiponectin and bone mass density. Lipids Health Dis 2008; 7: 1-4
• 31 Pluijm SM, Visser M, Smit JH, Popp-Snijders C, Roos JC, Lips P. Determinants of bone mineral density in older men and women: body composition as mediator. J Bone Miner Res 2001; 16: 2142-2151
• 32 Reid IR. Relationships among body mass, its components, and bone. Bone 2002; 31: 547-555
• 33 Clark EM, Ness AR, Tobias JH. Adipose tissue stimulates bone growth in prepubertal children. J Clin Endocrinol Metab 2006; 91: 2534-2541
• 34 Albala C, Yanez M, Devoto E, Sostin C, Zeballos L, Santos JL. Obesity as a protective factor for postmenopausal osteoporosis. Int J Obes Relat Metab Disord 1996; 20: 1027-1032
• 35 Klein KO, Larmore KA, de Lancey E, Brown JM, Considine RV, Hassink SG. Effect of obesity on estradiol level, and its relationship to leptin, bone maturation, and bone mineral density in children. J Clin Endocrinol Metab 1998; 83: 3469-3475
• 36 Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546
• 37 Thomas T, Burguera B, Melton 3rd LJ, Atkinson EJ, O’Fallon WM, Riggs BL, Khosla S. Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density. Bone 2001; 29: 114-120
• 38 Blain H, Vuillemin A, Guillemin F, Durant R, Hanesse B, de Talance N, Doucet B, Jeandel C. Serum leptin level is a predictor of bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2002; 87: 1030-1035
• 39 Maor G, Rochwerger M, Segev Y, Phillip M. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Miner Res 2002; 17: 1034-1043
• 40 Plagemann A, Harder T, Rake A, Waas T, Melchior K, Ziska T, Rohde W, Dörner G. Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. J Neuroendocrinol 1999; 11: 541-546
• 41 Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch Biochem Biophys 2010; 503: 129-136
• 42 Ben-Sholmo A, Hagag P, Evans S, Weiss M. Early postmenopausal bone loss in hyperthyroidism. Maturitas 2001; 39: 19-27
• 43 Murphy E, Gluer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healty euthyroid postmenopausal women. J Clin Endocrinol Metab 2010; 95: 3173-3181
• 44 Eriksen EF, Moskelide L, Melsen F. Kinetics of trabecular bone resorption and formation in hypothyroidism: evidence for a positive balance per remodeling cycle. Bone 1986; 7: 101-108
• 45 Madeira E, Mafort TT, Madeira M, Guedes EP, Moreira RO, de Mendonça LM, Lima IC, de Pinho PR, Lopes AJ, Farias ML. Lean mass as a predictor of bone density and microarchitecture in adult obese individuals with metabolic syndrome. Bone 2014; 59: 89-92
• 46 Reid IR, Ames R, Evans MC, Sharpe S, Gamble G, France JT, Lim TM, Cundy TF. Determinants of total body and regional bone mineral density in normal postmenopausal women – a key role for fat mass. J Clin Endocrinol Metab 1992; 75: 45-51
• 47 Iwaniec UT, Dube MG, Boghossian S, Song H, Helferich WG, Turner RT, Kalra SP. Body mass influences cortical bone mass independent of leptin signaling. Bone 2009; 44: 404-412
• 48 Seeman E, Delmas PD. Bone quality – the material and structural bias of bone strength and fragility. N Engl J Med 2006; 354: 2250-2261
• 49 Feldkamp LA, Goldstein SA, Parfitt AM, Jesion G, Kleerekoper M. The direct examination of three dimensional bone architecture in vitro by computed tomography. J Bone Miner Res 1989; 4: 3-11
• 50 Ma H, Turpeinen T, Silvennoinen M, Torvinen S, Rinnankoski-Tuikka R, Kainulainen H, Timonen J, Kujala UM, Rahkila P, Suominen H. Effects of diet-induced obesity and voluntary wheel running on the microstructure of the murine distal femur. Nutr Metab (Lond) 2011; 8: 1-11
• 51 Hildebrand T, Rüegsegger P. A new method for the model-independent assessment of thickness in three-dimensional images. J Microsc 1997; 185: 67-75
• 52 Eckstein F, Matsuura M, Kuhn V, Priemel M, Müller R, Link TM, Lochmüller EM. Sex differences of human trabecular bone microstructure in aging are site-dependent. J Bone Miner Res 2007; 22: 817-824
• 53 Xu Y, Li D, Chen Q, Fan Y. Full supervised learning for osteoporosis diagnosis using micro-CT images. Microsc Res Tech 2013; 76: 333-341
• 54 Saha PK, Xu Y, Duan H, Heiner A, Liang GY. Volumetric topological analysis: A novel approach for trabecular bone classification on the continuum between plates and rods. IEEE Trans Med Imaging 2010; 29: 1821-1838
• 55 Kleerekoper M, Villanueva AR, Stanciu J, Rao DS, Parfitt AM. The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 1985; 37: 594-597
• 56 Hahn M, Vogel M, Kempa MP, Delling G. Trabecular bone pattern factor-a new parameter for simple quantification of bone microarchitecture. Bone 1992; 13: 327-330
• 57 Heep H, Wedemeyer C, Wegner A, Hofmeister S, von Knoch M. Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading. Int J Biol Sci 2008; 4: 169-175
• 58 Brahmabhatt V, Rho J, Bernardis L, Gillespie R, Ziv I. The effects of dietary-induced obesity on the biomechanical properties of femora in male rats. Int J Obes Relat Metab Disord 1998; 22: 813-818
• 59 Lee AJ, Hodges S, Eastell R. Measurement of osteocalcin. Ann Clin Biochem 2000; 37: 432-446
• 60 Ip TY, Peterson J, Byrner R, Tou JC. Bone responses to body weight and moderate treadmill exercising in growing male obese (fa/fa) and lean Zucker rats. J Musculoskelet Neuronal Interact 2009; 9: 155-166
• 61 Looker AC, Bauer DC, Chesnut III CH, Gundberg CM, Hochberg MC, Klee G, Kleerekoper M, Watts NB, Bell NH. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporos Int 2000; 11: 467-480
• 62 Egan E, Reilly T, Giacomoni M, Redmond L, Turner C. Bone mineral density among female sports participants. Bone 2006; 38: 227-233
• 63 Bréban S, Chappard C, Jaffré C, Benhamou CL. Hypoleptinaemia in extreme body mass models: the case of international rugby players. J Sci Med Sport 2010; 13: 479-484
• 64 Fukumoto S, Martin TJ. Bone as an endocrine organ. Trends Endocrinol Metab 2009; 20: 230-236
• 65 Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130: 456-469
• 66 Lee NK, Karsenty G. Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metab 2008; 19: 161-166
• 67 Confavreux CB, Levine RL, Karsenty G. A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol 2009; 310: 21-29
• 68 Gravenstein KS, Napora JK, Short RG, Ramachandran R, Carlson OD, Metter EJ, Ferrucci L, Egan JM, Chia CW. Crosssectional evidence of a signaling pathway from bone homeostasis to glucose metabolism. J Clin Endocrinol Metab 2011; 96: E884-E890
• 69 Kanazawa I, Yamaguchi T, Tada Y, Yamauchi M, Yano S, Sugimoto T. Serum osteocalcin level is positively associated with insulin sensitivity and secretion in patients with type 2 diabetes. Bone 2011; 48: 720-725
• 70 Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol 2007; 157: 225-232
• 71 Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest 1985; 76: 370-373
• 72 Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA. The relationship between obesity and serum 1,25- dihydroxyvitamin D concentrations in healthy adults. J Clin Endocrinol Metab 2004; 89: 1196-1199
• 73 Lima N, da S, de Moura EG, Passos MC, Nogueira Neto FJ, Reis AM, de Oliveira E, Lisboa PC. Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br J Nutr 2011; 105: 1405-1413
• 74 de Albuquerque Maia L, Lisboa PC, de Oliveira E, da Silva Lima N, da Costa CA, de Moura EG. Two Models of Early Weaning Decreases Bone Structure by Different Changes in Hormonal Regulation of Bone Metabolism in Neonate Rat. Horm Metab Res 2013; 45: 332-337
• 75 Nobre JL, Lisboa PC, Lima Nda S, Franco JG, Nogueira Neto JF, de Moura EG, de Oliveira E. Calcium supplementation prevents obesity, hyperleptinaemia and hyperglycaemia in adult rats programmed by early weaning. Br J Nutr 2012; 107: 979-988
• 76 Devlin MJ, Bouxsein ML. Influence of pre- and peri-natal nutrition on skeletal acquisition and maintenance. Bone 2012; 50: 444-451
• 77 Paniagua MA, Malphurs JE, Samos LF. BMI and low bone mass in an elderly male nursing home population. Clin Interv Aging 2006; 1: 283-287
• 78 Chung W, Lee J, Ryu OH. Is the negative relationship between obesity and bone mineral content greater for older women?. J Bone Miner Metab 2013;
• 79 Gower BA, Casazza K. Divergent effects of obesity on bone health. J Clin Densitom 2013; 16: 450-454
• 80 Pramojanee SN, Phimphilai M, Kumphune S, Chattipakorn N, Chattipakorn SC. Decreased jaw bone density and osteoblastic insulin signaling in a model of obesity. J Dent Res 2013; 92: 560-565
• 81 Hage RE, Bachour F, Sebaaly A, Issa M, Zakhem E, Maalouf G. The Influence of Weight Status on Radial Bone Mineral Density in Lebanese Women. Calcif Tissue Int 2013;
• 82 Salamat MR, Salamat AH, Abedi I, Janghorbani M. Relationship between Weight, Body Mass Index, and Bone Mineral Density in Men Referred for Dual-Energy X-Ray Absorptiometry Scan in Isfahan, Iran. J Osteoporos 2013; 2013: 205963