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Evidence of a link between resting energy expenditure and bone remodelling, glucose homeostasis and adipokine variations in adolescent girls with anorexia nervosa

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Abstract

Summary

Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients.

Introduction

Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue-derived hormones in AN, a clinical model for reduced energy expenditure.

Methods

Fifty women with AN and 50 age-matched controls (mean age 18.1 ± 2.7 and 18.0 ± 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated.

Results

AN patients presented low aBMD at all bone sites. REEm, bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REEm was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA-IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration.

Conclusions

The strong interrelationships between REEm and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit short- and long-term bone demineralisation and hormonal alterations in AN patients.

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References

  1. Ferron M, Lacombe J (2014) Regulation of energy metabolism by the skeleton: osteocalcin and beyond. Arch Biochem Biophys 561C:137–146

    Article  Google Scholar 

  2. Karsenty G, Ferron M (2012) The contribution of bone to whole-organism physiology. Nature 481:314–320

    Article  PubMed  CAS  Google Scholar 

  3. 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 (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Confavreux CB, Levine RL, Karsenty G (2009) A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol 310:21–29

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG Jr, Chua SC Jr, Kim JK, Kaestner KH, Karsenty G (2008) The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol 183:1235–1242

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 105:5266–5270

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Fernandez-Real JM, Izquierdo M, Ortega F, Gorostiaga E, Gomez-Ambrosi J, Moreno-Navarrete JM, Fruhbeck G, Martinez C, Idoate F, Salvador J, Forga L, Ricart W, Ibanez J (2009) The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. J Clin Endocrinol Metab 94:237–245

    Article  PubMed  CAS  Google Scholar 

  8. Im JA, Yu BP, Jeon JY, Kim SH (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69

    Article  PubMed  CAS  Google Scholar 

  9. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791

    Article  PubMed  CAS  Google Scholar 

  10. Misra M, Soyka LA, Miller KK, Herzog DB, Grinspoon S, De Chen D, Neubauer G, Klibanski A (2003) Serum osteoprotegerin in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 88:3816–3822

    Article  PubMed  CAS  Google Scholar 

  11. Maimoun L, Guillaume S, Lefebvre P, Philibert P, Bertet H, Picot MC, Gaspari L, Paris F, Courtet P, Thomas E, Mariano-Goulart D, Bringer J, Renard E, Sultan C (2014) Role of sclerostin and Dickkopf-1 in the dramatic alteration in bone mass acquisition in adolescents and young women with recent anorexia nervosa. J Clin Endocrinol Metab 99:E582–E590

    Article  PubMed  CAS  Google Scholar 

  12. Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi S, Lee H, Mendes N, Snelgrove D, Meenaghan E, Misra M, Klibanski A (2014) Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int J Eat Disord 47:458–466

    Article  PubMed  PubMed Central  Google Scholar 

  13. Leonard MB, Shults J, Wilson BA, Tershakovec AM, Zemel BS (2004) Obesity during childhood and adolescence augments bone mass and bone dimensions. Am J Clin Nutr 80:514–523

    PubMed  CAS  Google Scholar 

  14. Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T, Takano K (2000) The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa. J Clin Endocrinol Metab 85:200–206

    PubMed  CAS  Google Scholar 

  15. Kosmiski L, Schmiege SJ, Mascolo M, Gaudiani J, Mehler PS (2014) Chronic starvation secondary to anorexia nervosa is associated with an adaptive suppression of resting energy expenditure. J Clin Endocrinol Metab 99:908–914

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Auwerx J, Staels B (1998) Leptin. Lancet 351:737–742

    Article  PubMed  CAS  Google Scholar 

  17. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207

    Article  PubMed  CAS  Google Scholar 

  18. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G (2004) Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A 101:3258–3263

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Hen R, Horvath TL, Karsenty G (2009) A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138:976–989

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H, Sizonenko PC, Bonjour JP (1992) Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab 75:1060–1065

    PubMed  CAS  Google Scholar 

  21. Hernandez CJ, Beaupre GS, Carter DR (2003) A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 14:843–847

    Article  PubMed  CAS  Google Scholar 

  22. Garcia FD, Grigioni S, Chelali S, Meyrignac G, Thibaut F, Dechelotte P (2010) Validation of the French version of SCOFF questionnaire for screening of eating disorders among adults. World J Biol Psychiatry 11:888–893

    Article  PubMed  Google Scholar 

  23. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33, quiz 34–57

    PubMed  Google Scholar 

  24. Roza AM, Shizgal HM (1984) The Harris Benedict equation reevaluated: resting energy requirements and the body cell mass. Am J Clin Nutr 40:168–182

    PubMed  CAS  Google Scholar 

  25. Kratzsch J, Lammert A, Bottner A, Seidel B, Mueller G, Thiery J, Hebebrand J, Kiess W (2002) Circulating soluble leptin receptor and free leptin index during childhood, puberty, and adolescence. J Clin Endocrinol Metab 87:4587–4594

    Article  PubMed  CAS  Google Scholar 

  26. Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Klibanski A (1989) Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab 68:548–554

    Article  PubMed  CAS  Google Scholar 

  27. Klibanski ABB, Schoenfeld DA, Herzog DB, Saxe VC (1995) The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 80:898–904

    PubMed  CAS  Google Scholar 

  28. Kooh SW, Noriega E, Leslie K, Muller C, Harrison JE (1996) Bone mass and soft tissue composition in adolescents with anorexia nervosa. Bone 19:181–188

    Article  PubMed  CAS  Google Scholar 

  29. Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, Matkovic V, Weaver C (2000) Peak bone mass. Osteoporos Int 11:985–1009

    Article  PubMed  CAS  Google Scholar 

  30. Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C (1986) Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest 78:1568–1578

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50:568–575

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Zhou B, Li H, Xu L, Zang W, Wu S, Sun H (2013) Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-kappaB signaling pathway. Endocrinology 154:1055–1068

    Article  PubMed  CAS  Google Scholar 

  33. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Bruning JC, Clemens TL (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 3:25–38

    Article  PubMed  CAS  Google Scholar 

  36. Misra M, Miller KK, Almazan C, Ramaswamy K, Aggarwal A, Herzog DB, Neubauer G, Breu J, Klibanski A (2004) Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. J Clin Endocrinol Metab 89:3486–3495

    Article  PubMed  CAS  Google Scholar 

  37. Ostrowska Z, Ziora K, Oswiecimska J, Swietochowska E, Szapska B, Wolkowska-Pokrywa K, Dyduch A (2012) RANKL/RANK/OPG system and bone status in females with anorexia nervosa. Bone 50:156–160

    Article  PubMed  CAS  Google Scholar 

  38. Urano A, Hotta M, Ohwada R, Araki M (2014) Vitamin K deficiency evaluated by serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa with bone loss. Clin Nutr S0261–5614

  39. Grinspoon SBH, Lee K, Anderson E, Herzog D, Klibanski A (1996) Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J Clin Endocrinol Metab 81:3864–3870

    PubMed  CAS  Google Scholar 

  40. LA Soyka GS, Levitsky LL, Herzog DB, Klibanski A (1999) The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab 84:4489–4496

    PubMed  CAS  Google Scholar 

  41. Misra M, Miller KK, Cord J, Prabhakaran R, Herzog DB, Goldstein M, Katzman DK, Klibanski A (2007) Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab 92:2046–2052

    Article  PubMed  CAS  Google Scholar 

  42. Misra M, Miller KK, Stewart V, Hunter E, Kuo K, Herzog DB, Klibanski A (2005) Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents. J Clin Endocrinol Metab 90:5082–5087

    Article  PubMed  CAS  Google Scholar 

  43. Tagami T, Satoh N, Usui T, Yamada K, Shimatsu A, Kuzuya H (2004) Adiponectin in anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 89:1833–1837

    Article  PubMed  CAS  Google Scholar 

  44. Housova J, Anderlova K, Krizova J, Haluzikova D, Kremen J, Kumstyrova T, Papezova H, Haluzik M (2005) Serum adiponectin and resistin concentrations in patients with restrictive and binge/purge form of anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 90:1366–1370

    Article  PubMed  CAS  Google Scholar 

  45. Haluzikova D, Dostalova I, Kavalkova P, Roubicek T, Mraz M, Papezova H, Haluzik M (2009) Serum concentrations of adipocyte fatty acid binding protein in patients with anorexia nervosa. Physiol Res 58:577–581

    PubMed  CAS  Google Scholar 

  46. Legroux-Gerot I, Vignau J, Biver E, Pigny P, Collier F, Marchandise X, Duquesnoy B, Cortet B (2010) Anorexia nervosa, osteoporosis and circulating leptin: the missing link. Osteoporos Int 21:1715–1722

    Article  PubMed  CAS  Google Scholar 

  47. Chan JL, Bluher S, Yiannakouris N, Suchard MA, Kratzsch J, Mantzoros CS (2002) Regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans. Diabetes 51:2105–2112

    Article  PubMed  CAS  Google Scholar 

  48. Krizova J, Papezova H, Haluzikova D, Parizkova J, Jiskra J, Kotrlikova E, Haas T, Haluzik M (2002) Soluble leptin receptor levels in patients with anorexia nervosa. Endocr Res 28:199–205

    Article  PubMed  CAS  Google Scholar 

  49. Pannacciulli N, Vettor R, Milan G, Granzotto M, Catucci A, Federspil G, De Giacomo P, Giorgino R, De Pergola G (2003) Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 88:1748–1752

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to express their thanks to the patients, the controls and their parents for their participation. This work was supported by the Centre Hospitalier Regional Universitaire (CHRU) of Montpellier (AOI UF 8751 and UF 8854) and a grant from the Société Française d’Endocrinologie Pédiatrique (SFEDP). Some of the biochemical kits were provided by Roche Diagnostics.

Conflicts of interest

Laurent Maimoun, Sebastien Guillaume, Patrick Lefebvre, Pascal Philibert, Helena Bertet, Marie-Christine Picot, Laura Gaspari, Françoise Paris, Maude Seneque, Anne-Marie Dupuys, Philippe Courtet, Eric Thomas, Denis Mariano-Goulart, Jacques Bringer, Eric Renard, and Charles Sultan declare that they have no conflict of interest.

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Maïmoun, L., Guillaume, S., Lefebvre, P. et al. Evidence of a link between resting energy expenditure and bone remodelling, glucose homeostasis and adipokine variations in adolescent girls with anorexia nervosa. Osteoporos Int 27, 135–146 (2016). https://doi.org/10.1007/s00198-015-3223-x

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