European Journal of Nutrition

, Volume 48, Issue 3, pp 137–144 | Cite as

Biotin deficiency in mice is associated with decreased serum availability of insulin-like growth factor-I

  • Armida Báez-SaldañaEmail author
  • Gabriel Gutiérrez-Ospina
  • Jesús Chimal-Monroy
  • Cristina Fernandez-Mejia
  • Rafael Saavedra



Biotin deficiency leads to decreased weight and nose-rump length in mice.

Aim of the study

The mechanisms underlying this impairment in body growth are yet unclear. Biotin restriction, however, could affect the availability of growth hormone (GH) and/or insulin like growth factor-I (IGF-I) since both hormones control body growth. We then conducted a correlative study aimed at establishing whether biotin dietary restriction is associated with decreased GH/IGF-I serum concentrations.


Levels of GH and IGF-I were measured through ELISA in serum samples of male BALB/cAnN mice fed with: 1] standard chow diet (control diet); 2] 30% egg-white biotin-deficient diet; or 3] 30% egg-white diet supplemented with 16.4 µmol biotin per kilogram (biotin sufficient diet). Relative food consumption, as adjusted per gram of body weight, was also determined. GH and IGF-I measurements were taken individually for 20 weeks beginning at the postnatal week 3, when the animals started consuming the corresponding diets. In addition, femur’s weight and longitudinal growth and the organization of its growth plate were all analyzed as indicators of GH/IGF-I function.


No differences in relative food consumption were observed among the three groups of mice along the experimental period that was evaluated. IGF-I serum levels, but not GH ones, were decreased in biotin deficient mice. These animals also showed decreased femur’s longitudinal growth, speed of lengthening and weight gain, as well as shorter and disorganized growth plates.


This study shows that biotin dietary restriction is indeed associated with decreased availability of IGF-I and diminished long bone growth and elongation. These conditions could explain the impairment of longitudinal body growth previously reported in biotin deficient mice. Although cause-effect studies are still needed, we believe our results support the notion that biotin might modulate the availability of IGF-I.


body growth body size bone growth nutrition vitamins growth hormone 



Biotin deficient


Biotin sufficient


Somatotropin or growth hormone


Insulin-like growth factor I



We thank to Georgina Díaz for providing animal care assistance, to David Garciadiego-Cázares for the histological processing, and to Georgina Del Vecchyo for her encouragement in achieving femur measurements. Authors are also grateful to Dr. David Riddle for helpful criticisms and editing.


  1. 1.
    Báez-Saldaña A, Ortega E (2004) Biotin deficiency blocks thymocyte maturation, accelerates thymus involution, and decreases nose-rump length in mice. J Nutr 179:1970–1977Google Scholar
  2. 2.
    Báez-Saldaña A, Diaz G, Espinoza B, Ortega E (1998) Biotin deficiency induces changes in subpopulations of spleen lymphocytes in mice. Am J Clin Nutr 67:431–437Google Scholar
  3. 3.
    Bain SD, Newbrey JW, Watkins BA (1988) Biotin deficiency may alter tibiotarsal bone growth and modeling in broiler chicks. Poult Sci 67:590–595Google Scholar
  4. 4.
    Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82Google Scholar
  5. 5.
    Balnave D (1997) Clinical symptoms of biotin deficiency in animals. Am J Clin Nutr 30:1408–1413Google Scholar
  6. 6.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  7. 7.
    Breur GJ, VanEnkevort BA, Farnum CE, Wilsman NJ (1991) Linear relationship between the volume of hypertrophic chondrocytes and the rate of longitudinal bone growth in growth plates. J Orth Res 9:348–359CrossRefGoogle Scholar
  8. 8.
    Clark RG, Mortensen DL, Carlsson LM, Spencer SA, McKay P, Mulkerrin M, Moore J, Cunningham BC (1996) Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat. Endocrinology 137:4308–4315CrossRefGoogle Scholar
  9. 9.
    Dakshinamurti K, Chauhan J (1998) Biotin. Vitam Horm 45:337–384CrossRefGoogle Scholar
  10. 10.
    Efstratiadis A (1998) Genetics of mouse growth. Int J Dev Biol 42:955–976Google Scholar
  11. 11.
    Fielder PJ, Mortensen DL, Mallet P, Carlsson B, Baxter RC, Clark RG (1996) Differential long-term effects of insulin-like growth factor-I (IGF-I) growth hormone (GH), and IGF-I plus GH on body growth and IGF binding proteins in hypophysectomized rats. Endocrinology 137:1913–1920CrossRefGoogle Scholar
  12. 12.
    Fliesen T, Maiter D, Gerard G, Underwood LE, Maes M, Ketelsleger J-M (1989) Reduction of serum insulin-like growth factor-I by dietary protein restriction is age dependent. Pediatr Res 26:415–419CrossRefGoogle Scholar
  13. 13.
    Friedrich W (1988) Vitamins. Walter de Gruyter, BerlinGoogle Scholar
  14. 14.
    Fryburg DA (1994) Insulin-like growth factor I exerts growth hormone and insulin-like actions on human muscle protein metabolism. Am J Physiol 267:E331–E336Google Scholar
  15. 15.
    Fryburg DA, Jahn LA, Hill SA, Oliveras DM, Barrett EJ (1995) Insulin and insulin-like growth factor I enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms. J Clin Invest 96:1722–1729CrossRefGoogle Scholar
  16. 16.
    Furukawa Y, Numazawa T, Fukazawa H, Ikai M, Ohinata K, Maebashi M, Kim DH, Ito M, Komai M, Kimura S (1993) Biochemical consequences of biotin deficiency in osteogenic disorder shionogi rats. Int J Vitam Nutr Res 63:129–134Google Scholar
  17. 17.
    Garciadiego-Cázares D, Rosales C, Katoh M, Chimal-Monroy J (2004) Coordination of chondrocyte differentiation and joint formation by α5β1 integrin in the developing appendicular skeleton. Development 131:4735–4742CrossRefGoogle Scholar
  18. 18.
    Harada N, Oda Z, Hara Y, Fujinami K, Okawa M, Ohbuchi K, Yonemoto M, Ikeda Y, Ohkawi K, Aragane K, Tamai Y, Kisunoki J (2007) Hepatic de novo lipogenesis is present in liver specific ACC-1 deficient mice. Mol Cell Biol 27:1881–1888CrossRefGoogle Scholar
  19. 19.
    Harel Z, Tannebaum GS (1993) Dietary protein restriction impairs both spontaneous and growth hormone-releasing factor-stimulated growth hormone release in the rat. Endocrinology 133:1035–1043CrossRefGoogle Scholar
  20. 20.
    Hunziker EB, Schenk RK (1989) Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats. J Physiol (Lond) 414:55–71Google Scholar
  21. 21.
    Hunziker EB, Wagner J, Zapf J (1994) Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J Clin Inv 93:1078–1086CrossRefGoogle Scholar
  22. 22.
    Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34Google Scholar
  23. 23.
    Kostyo JL (1968) Rapid effects of growth hormone on aminoacid transport and protein synthesis. Ann NY Acad Sci 148:389–407CrossRefGoogle Scholar
  24. 24.
    Kothapalli N, Camporeale G, Kueh A, Chew YC, Oommen AM, Griffin JB, Zempleni J (2005) Biological functions of biotinylated histones. J Nutr Biochem 16:446–448CrossRefGoogle Scholar
  25. 25.
    LeRoith D, Bondy C, Yakar S, Liu J, Butler A (2001) The somatomedin hypothesis. Endocr Rev 22:53–74CrossRefGoogle Scholar
  26. 26.
    Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229:141–162CrossRefGoogle Scholar
  27. 27.
    MacLeod JN, Pampori NA, Shapiro BH (1991) Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice. J Endocrinol 131:395–399CrossRefGoogle Scholar
  28. 28.
    Mejia WN, Yakar S, Sanchez-Gomez M, Umana PA, Setser J, LeRoith D (2002) Protein calorie restriction affects nonhepatic IGF-I production and the lymphoid system: studies using the liver-specific IGF-I gene-deleted mouse model. Endocrinology 143:2233–2241CrossRefGoogle Scholar
  29. 29.
    Mejia-Naranjo W, Yakar S, Bernal R, LeRoith D, Sanchez-Gomez M (2003) Regulation of the splenic somatotropic axis by dietary protein and insulin-like growth factor-I in the rat. Growth Horm IGF Res 13:254–263CrossRefGoogle Scholar
  30. 30.
    Mock DM (1990) Evidence for a pathogenic role of w6 polyunsaturated fatty acids in the cutaneous manifestations of biotin deficiency. J Ped Gastro Nutr 10:222–229CrossRefGoogle Scholar
  31. 31.
    Montgomery R, Dryer RL, Conway TW, Spector AA (1980) Biochemistry: a case-oriented approach. The CV Mosby Company, St. LouisGoogle Scholar
  32. 32.
    Nijhout HF (2003) The control of growth. Development 130:5683–5687CrossRefGoogle Scholar
  33. 33.
    Ohlsson C, Nilsson A, Isaksson OGP, Lindahl A (1992) Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate. Proc Natl Acad Sci USA 89:9826–9830CrossRefGoogle Scholar
  34. 34.
    Ohlsson C, Bengtsson B-A, Isaksson OGP, Andreassen TT, Slootweg MC (1998) Growth hormone and bone. Endocr Rev 19:55–79CrossRefGoogle Scholar
  35. 35.
    Patel MS, Mistry SP (1968) Effect of biotin deficiency on food intake and body and organ weights of male albino rats. Growth 32:175–187Google Scholar
  36. 36.
    Pattie WA, Williams AJ (1967) Selection for weaning weight in Merino sheep: 3. Maintenance requirements and the efficiency of conversion of feed to wool in mature ewes. Aust J Exp Agric Anim Husb 7(25):117–125CrossRefGoogle Scholar
  37. 37.
    Renaville R, Hammadi M, Potetelle D (2003) Role of the somatotropic axis in the mammalian metabolism. Domest Anim Endocrinol 23:351–360CrossRefGoogle Scholar
  38. 38.
    Rodriguez-Melendez R, Zempleni J (2003) Regulation of gene expression by biotin (review). J Nutr Biochem 14:680–690CrossRefGoogle Scholar
  39. 39.
    Romero-Navarro G, Cabrera-Valladares G, German MS, Matschinsky FM, Velazquez A, Wang J, Fernandez-Mejia C (1999) Biotin regulation of pancreatic glucokinase and insulin in primary cultured rat islets and in biotin-deficient rats. Endocrinology 140:4595–4600CrossRefGoogle Scholar
  40. 40.
    Schrijver J, Dias T, Hommes FA (1979) Some biochemical observations on biotin deficiency in the rat as a model for human Pyruvate carboxylase deficiency. Nutr Metab 23:179–191CrossRefGoogle Scholar
  41. 41.
    Stewart CEH, Rotwein P (1996) Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 76:1005–1026Google Scholar
  42. 42.
    Thissen JP, Ketelslegers JM, Underwood LE (1994) Nutritional regulation of the insulin-like growth factors. Endocr Rev 15:80–101Google Scholar
  43. 43.
    Wallenius K, Sjögren K, Peng X-D, Park S, Wallenius V, Liu J-L, Umaerus M, Wennbo H, Isaksson O, Frohman L, Kineman R, Ohlson C, Jansson J-O (2001) Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. Endocrinology 142:4762–4770CrossRefGoogle Scholar
  44. 44.
    Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA (2004) Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 180:247–255CrossRefGoogle Scholar
  45. 45.
    Yakar S, Rossen CJ, Beamer WG, Ackert-Bicknell ChL, Wu Y, Liu J-L, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D (2002) Circulating levels of IGF-I directly regulate bone growth and density. J Clin Invest 110:771–781Google Scholar
  46. 46.
    Zeigler HP, Green HL, Siegel J (1972) Food and water intake and weight regulation in the pigeon. Physiol Behav 8:127–134CrossRefGoogle Scholar
  47. 47.
    Zempleni J (2005) Uptake, localization, and noncarboxylase roles of biotin. Annu Rev Nutr 25:175–196CrossRefGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2009

Authors and Affiliations

  • Armida Báez-Saldaña
    • 1
    Email author
  • Gabriel Gutiérrez-Ospina
    • 1
  • Jesús Chimal-Monroy
    • 2
  • Cristina Fernandez-Mejia
    • 3
  • Rafael Saavedra
    • 4
  1. 1.Depto. de Biología Celular y Fisiología, Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMéxicoMéxico
  2. 2.Depto. de Medicina Genómica y Toxicología AmbientalInstituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de MéxicoMéxicoMéxico
  3. 3.Unidad de Genética de la NutriciónInstituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de MéxicoMéxicoMéxico
  4. 4.Depto. de Inmunología, Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMéxicoMéxico

Personalised recommendations