Modulation of circulating IGF-I and IGFBP-3 levels by hormonal regulators of energy homeostasis in obese children

 

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Abstract

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are key factors in the control of somatic growth. Recent work revealed a critical role for the transcription factor STAT5b in GH stimulated IGF-I gene expression. In obesity, the normal regulation of the GH/IGF-I axis is disturbed, with normal levels of circulating IGF-I despite blunted GH secretion. We hypothesized that leptin or other hormonal regulators of energy homeostasis, which can activate Stat5b-regulated gene expression or exert an effect on GH secretion, might be able to substitute for GH in terms of IGF-I synthesis. Thus, the aim of this study was to identify potential regulators of IGF-I serum levels in obesity with a particular focus on the interaction of leptin and IGF-I. In a cross-sectional study, we measured hormonal and auxiological parameters in 99 obese children who were referred to our obesity outpatient clinic and analysed correlations between unadjusted hormone levels and between hormone concentrations expressed as SDS values, adjusted for sex, age, and/or puberty and BMI. Serum concentrations of IGF-I correlated highly significant with IGFBP-3, leptin, fasting ghrelin and insulin (p<0.001). However, when expressing hormone levels as SDS values, only leptin SDS and IGFBP-3 SDS correlated significantly with IGF-I SDS (p<0.01). This correlation between leptin SDS and IGF-I SDS was more pronounced in prepubertal and in male subjects, with increasing IGF-I SDS values paralleling an increase in leptin SDS tertiles in prepubertal subjects. In linear regression analyses, leptin SDS, IGFBP-3 SDS and BMI SDS contributed significantly to the variation of IGF-I SDS values, and explained 53.3% of the variability of IGF-I SDS levels in male subjects.

Summary and conclusions: In summary, we demonstrated a strong correlation of age and sex-adjusted standard deviation scores (SDS) for IGF-I and leptin in obese children, which is modulated by sex, pubertal stage and body weight. Whether this association results from a direct induction of hepatic IGF-I gene expression by leptin or reflects a more complex interrelationship between IGF-I and obesity-related factors should be subject of future research.

References

• 1 Argente J, Caballo N, Barrios V, Pozo J, Munoz MT, Chowen JA, Hernandez M. Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in prepubertal children with exogenous obesity: effect of short- and long-term weight reduction.  J Clin Endocrinol Metab. 1997;  82 2076-2083
  CrossrefPubMedGoogle Scholar
• 2 Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.  J Clin Endocrinol Metab. 2001;  86 4753-4758
  CrossrefPubMedGoogle Scholar
• 3 Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Muller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone.  J Clin Endocrinol Metab. 1997;  82 2904-2910
  CrossrefPubMedGoogle Scholar
• 4 Blum WF, Schweizer R. Insulin-like growth factors and their binding proteins. In: Ranke MB Diagnostics of endocrine function in children and adolescents. 3rd Edition. pp 166-1 S. Karger AG, Basel (CH) 2003
  Google Scholar
• 5 Carvalheira JB, Ribeiro EB, Folli F, Velloso LA, Saad MJ. Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver.  Biol Chem. 2003;  384 151-159
  CrossrefPubMedGoogle Scholar
• 6 Cole TJ. The LMS method for constructing normalized growth standards.  Eur J Clin Nutr. 1990;  44 45-60
  PubMedGoogle Scholar
• 7 Colletti RB, Copeland KC, Devlin JT, Roberts JD, McAuliffe TL. Effect of obesity on plasma insulin-like growth factor-I in cancer patients.  Int J Obes. 1991;  15 523-527
  PubMedGoogle Scholar
• 8 Conover CA, Lee PD, Kanaley JA, Clarkson JT, Jensen MD. Insulin regulation of insulinlike growth factor binding protein-I in obese and nonobese humans.  J Clin Endocrinol Metab. 1992;  74 1355-1360
  CrossrefPubMedGoogle Scholar
• 9 Copeland KC, Colletti RB, Devlin JT, McAuliffe TL. The relationship between insulin-like growth factor-I, adiposity, and aging.  Metabolism. 1990;  39 584-587
  CrossrefPubMedGoogle Scholar
• 10 Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations.  Endocr Rev. 1989;  10 68-91
  CrossrefPubMedGoogle Scholar
• 11 El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flyer JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.  J Clin Invest. 2000;  105 1827-1832
  CrossrefPubMedGoogle Scholar
• 12 Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE, Orskov H. Free insulin-like growth factors in human obesity.  Metabolism. 1995;  44 37-44
  CrossrefPubMedGoogle Scholar
• 13 Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC. Defective STAT signaling by the leptin receptor in diabetic mice.  Proc Natl Acad Sci USA. 1996;  93 6231-6235
  CrossrefPubMedGoogle Scholar
• 14 Haqq AM, Farooqi IS, O’Rahilly S, Stadler DD, Rosenfeld RG, Pratt KL, LaFranchi SH, Purnell JQ. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome.  J Clin Endocrinol Metab. 2003;  88 174-178
  CrossrefPubMedGoogle Scholar
• 15 Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, Berberoglu M, Rosenfeld RG. Severe growth hormone insufficiency resulting from total absence of Stat5b.  J Clin Endocrinol Metab. 2005;  , (ePub ahead of print)
  PubMedGoogle Scholar
• 16 Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men.  J Clin Endocrinol Metab. 1991;  73 1081-1088
  CrossrefPubMedGoogle Scholar
• 17 Janssen JA, van der Toorn FM, Hofland LJ, van Koetsveld P, Broglio F, Ghigo E, Lamberts SW, Jan van der Lely A. Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy.  Eur J Endocrinol. 2001;  145 711-716
  CrossrefPubMedGoogle Scholar
• 18 Kiess W, Klammt J, Hanze J, Blum WF, Berthold A, Seidel B, Kratzsch J. Evidence against a direct effect of leptin in insulin-like growth factor-I (IGF-I), IGFBP-2 and IGF-I receptor expression in human SK-N-MC neuroepithelioma cells.  Regul Pept. 2005;  in press
  PubMedGoogle Scholar
• 19 Kletter GB, Cemeroglu AP, Foster CM, Frayo RS, Cummings DE. Serum ghrelin concentrations after an overnight fast in children and adolescents. A cross section study.  Proceedings of the 84th annual meeting of the endocrine society. 2002;  , OR 23-5
  PubMedGoogle Scholar
• 20 Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG. Growth hormone insensitivity associated with a STAT5b mutation.  N Engl J Med. 2003;  349 1139-1147
  CrossrefPubMedGoogle Scholar
• 21 Kojima M, Hosoda H, Date Yakazato M, Matsuo H, Kangawa K. Ghrelin is a growthhormone- releasing acetylated peptide from stomach.  Nature. 1999;  402 656-660
  CrossrefPubMedGoogle Scholar
• 22 Kromeyer-Hauschild K, Wabitsch M, Geller F, Ziegler A, Geiss HC, Hesse V, v Hippel, Jaeger U, Johnsen D, Kiess W, Korte W, Kunze D, Menner K, Müller M, Niemann-Pilatus A, Remer Th, Schaefer F, Wittchen HU, Zabransky S, Zellner K, Hebebrand J. Percentiles of body mass index in children and adolescents evaluated from different regional German studies.  Monatsschr Kinderheilkd. 2001;  149 807-818
  CrossrefPubMedGoogle Scholar
• 23 Lautala P, Akerblom HK, Viikari J, Louhivuori K, Uhari M, Dahlstrom S, Dahl M, Lahde PL, Pesonen E, Pietikainen M, Suninen P, Knip M. Atherosclerosis precursors in Finnish children and adolescents. VII. Serum immunoreactive insulin.  Acta Paediatr Scand Suppl. 1985;  318 127-133
  PubMedGoogle Scholar
• 24 Loche S, Cappa M, Borrelli P, Faedda A, Crino A, Cella SG, Corda R, Muller EE, Pintor C. Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition.  Clin Endocrinol. 1987;  27 145-153
  CrossrefPubMedGoogle Scholar
• 25 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
  CrossrefPubMedGoogle Scholar
• 26 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
  Google Scholar
• 27 Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin.  Clin Chem. 2004;  50 1511-1525
  CrossrefPubMedGoogle Scholar
• 28 Mesotten D, Wouters PJ, Peeters RP, Hardman KV, Holly JM, Baxter RC, Van den Berghe G. Regulation of the somatotropic axis by intensive insulin therapy during protracted critical illness.  J Clin Endocrinol Metab. 2004;  89 3105-3113
  CrossrefPubMedGoogle Scholar
• 29 Münzberg H, Myers MG. Molecular and anatomical determinants of central leptin resistance.  Nature Neuroscience. 2005;  8 566-570
  CrossrefPubMedGoogle Scholar
• 30 Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone.  Int J Obes Relat Metab Disord. 1997;  21 355-359
  CrossrefPubMedGoogle Scholar
• 31 Nyomba BL, Johnson M, Berard L, Murphy LJ. Relationship between serum leptin and the insulin-like growth factor-I system in humans.  Metabolism. 1999;  48 840-844
  CrossrefPubMedGoogle Scholar
• 32 Poykko SM, Ukkola O, Kauma H, Kellokoski E, Horkko S, Kesaniemi YA. The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes.  Diabetologia. 2005;  48 309-316
  CrossrefPubMedGoogle Scholar
• 33 Qian H, Azain MJ, Hartzell DL, Baile CA. Increased leptin resistance as rats grow to maturity.  Proc Soc Exp Biol Med. 1998;  219 160-165
  PubMedGoogle Scholar
• 34 Rosskamp R, Becker M, Soetadji S. Circulating somatomedin-C levels and the effect of growth hormone-releasing factor on plasma levels of growth hormone and somatostatin-like immunoreactivity in obese children.  Eur J Pediatr. 1987;  146 48-50
  CrossrefPubMedGoogle Scholar
• 35 Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity.  Int J Obes Relat Metab Disord. 1999;  23 260-271
  CrossrefPubMedGoogle Scholar
• 36 Smith CP, Dunger DB, Williams AJ, Taylor AM, Perry LA, Gale EA, Preece MA, Savage MO. Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life.  J Clin Endocrinol Metab. 1989;  68 932-937
  CrossrefPubMedGoogle Scholar
• 37 Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses.  Cell. 1998;  93 841-850
  CrossrefPubMedGoogle Scholar
• 38 Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors.  Endocr Rev. 1994;  15 80-101
  CrossrefPubMedGoogle Scholar
• 39 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents.  Nature. 2000;  19 908-913
  PubMedGoogle Scholar
• 40 Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G. Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man.  J Clin Endocrinol Metab. 1991;  72 51-59
  CrossrefPubMedGoogle Scholar
• 41 Whatmore AJ, Hall CM, Jones J, Westwood M, Clayton PE. Ghrelin concentrations in healthy children and adolescents.  Clin Endocrinol (Oxf). 2003;  59 649-654
  CrossrefPubMedGoogle Scholar
• 42 Woelfle J, Billiard J, Rotwein P. Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b.  J Biol Chem. 2003a;  278 22696-22702
  CrossrefPubMedGoogle Scholar
• 43 Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation.  J Biol Chem. 2003;  278 51261-51266
  CrossrefPubMedGoogle Scholar
• 44 Woelfle J, Rotwein P. In vivo regulation of growth hormone-stimulated gene transcription by STAT5b.  Am J Physiol Endocrinol Metab. 2004;  286 E393-401
  PubMedGoogle Scholar

Correspondence

J. F. Woelfle

Children's Hospital

University of Bonn

Adenauerallee 119

53113 Bonn, Germany

Phone: + +49/228/28 733 333

Fax: + +49/228/28 733 314

Email: joachim.woelfle@ukb.uni-bonn.de