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Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment

Abstract

OBJECTIVE: To observe the chronic effects of human growth hormone (hGH) and AOD9604 (a C-terminal fragment of hGH) on body weight, energy balance, and substrate oxidation rates in obese (ob/ob) and lean C57BL/6Jmice. In vitro assays were used to confirm whether the effects of AOD9604 are mediated through the hGH receptor, and if this peptide is capable of cell proliferation via the hGH receptor.

METHOD: Obese and lean mice were treated with hGH, AOD or saline for 14 days using mini-osmotic pumps. Body weight, caloric intake, resting energy expenditure, fat oxidation, glucose oxidation, and plasma glucose, insulin and glycerol were measured before and after treatment. BaF-BO3 cells transfected with the hGH receptor were used to measure in vitro 125I-hGH receptor binding and cell proliferation.

RESULTS: Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis). Unlike hGH, however, AOD9604 did not induce hyperglycaemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH.

CONCLUSIONS: Both hGH and its C-terminal fragment reduce body weight gain, increase fat oxidation, and stimulate lipolysis in obese mice, yet AOD9604 does not interact with the hGH receptor. Thus, the concept of hGH behaving as a pro-hormone is further confirmed. This data shows that fragments of hGH can act in a manner novel to traditional hGH-stimulated pathways.

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References

  1. Davidson MB . Effect of growth hormone on carbohydrate and lipid metabolism Endocr Rev 1987 8: 115–131.

    Article  CAS  Google Scholar 

  2. Dietz J, Schwartz J . Growth hormone alters lipolysis and hormone-sensitive lipase activity in 3T3-F442A adipocytes Metabolism 1991 40: 800–806.

    Article  CAS  Google Scholar 

  3. Boss O, Muzzin P, Giacobino J-P . The uncoupling proteins; a review Eur J Endocrinol 1998 139: 1–9.

    Article  CAS  Google Scholar 

  4. Watt PW, Finley E, Cork S, Clegg RA, Vernon RG . Chronic control of the beta- and alpha 2-adrenergic systems of sheep adipose tissue by growth hormone and insulin Biochem J 1991 273: (Pt 1): 39–42.

    Article  Google Scholar 

  5. Donkin SS, Chiu PY, Yin D, Louveau I, Swencki B, Vockroth J, Evock-Clover CM, Peters JL, Etherton TD . Porcine somatotrophin differentially down-regulates expression of the GLUT4 and fatty acid synthase genes in pig adipose tissue J Nutr 1996 126: 2568–2577.

    Article  CAS  Google Scholar 

  6. Spyer G, Ellard S, Hattersley A . Growth-hormone treatment and risk of diabetes Lancet 2000 355: 1913–1914.

    Article  CAS  Google Scholar 

  7. Carrel AL, Allen DB . Effects of growth hormone on body composition and bone metabolism Endocrine 2000 12: 163–172.

    Article  CAS  Google Scholar 

  8. Baumann G . Growth hormone heterogeneity in human pituitary and plasma Horm Res 1999 51: 2–6.

    CAS  PubMed  Google Scholar 

  9. Jeoung DI, Allen DL, Guller S, Yen V, Sonenberg M . Mitogenic and receptor activities of human growth hormone 108–129 J Biol Chem 1993 268: 22520–22524.

    CAS  PubMed  Google Scholar 

  10. Sinha YN, Jacobsen BP . Human growth hormone (hGH)-(44–191), a reportedly diabetogenic fragment of hGH, circulates in human blood: measurement by radioimmunoassay J Clin Endocrinol Metab 1994 78: 1411–1418.

    CAS  PubMed  Google Scholar 

  11. Lim N, Ng FM, Wu ZM, Ede N, Hearn MT . Hypoglycemic action of a novel constrained analog of human growth hormone (6–13) Endocrinology 1992 131: 835–840.

    CAS  PubMed  Google Scholar 

  12. Heffernan MA, Jiang WJ, Thorburn AW, Ng FM . Effects of oral administration of a synthetic fragment of human growth hormone on lipid metabolism Am J Physiol 2000 279: E501–E507.

    CAS  Google Scholar 

  13. Wu Z, Ng FM . Antilipogenic action of synthetic C-terminal sequence 177–191 of human growth hormone Biochem Mol Biol Int 1993 30: 187–196.

    CAS  PubMed  Google Scholar 

  14. Jiang WJ . Investigation into human Growth Hormone 177–191 peptides and analogues as anti-obesity agents PhD thesis, Monash University 1999

  15. Rowlinson SW, Behncken SN, Rowland JE, Clarkson RW, Strasburger CJ, Wu Z, Baumbach W, Waters MJ . Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies. A specific conformational change may be required for full-length receptor signaling J Biol Chem 1998 273: 5307–5314.

    Article  CAS  Google Scholar 

  16. Gobius KS, Rowlinson SW, Barnard R, Mattick SC, Waters MJ . The first disulphide loop of rabbit growth hormone receptor is required for binding to the hormone J Mol Endocrinol 1992 9: 213–220.

    Article  CAS  Google Scholar 

  17. Rowlinson SW, Waters MJ, Lewis UJ, Barnard R . Human growth hormone fragments 1–43 and 44–191: in vitro somatogenic activity and receptor binding characteristics in human and nonprimate systems Endocrinology 1996 137: 90–95.

    Article  CAS  Google Scholar 

  18. Casanueva FF, Dieguez C . Interaction between body composition, leptin and growth hormone status Baillieres Clin Endocrinol Metab 1998 12: 297–314.

    Article  CAS  Google Scholar 

  19. Natera SH, Jiang WJ, Ng FM . Reduction of cumulative body weight gain and adipose tissue mass in obese mice: response to chronic treatment with synthetic hGH 177–191 peptide Biochem Mol Biol Int 1994 33: 1011–1021.

    CAS  PubMed  Google Scholar 

  20. Cameron CM, Kostyo JL, Adamafio NA, Dunbar JC . Metabolic basis for the diabetogenic action of growth hormone in the obese (ob/ob) mouse Endocrinology 1987 120: 1568–1575.

    Article  CAS  Google Scholar 

  21. Marcus C, Margery V, Kamel A, Bronnegard M . Effects of growth hormone on lipolysis in humans Acta Paediatr 1994 406 (Suppl): 54–58.

    Article  CAS  Google Scholar 

  22. Vernon RG . GH inhibition of lipogenesis and stimulation of lipolysis in sheep adipose tissue: involvement of protein serine phosphorylation and dephosphorylation and phospholipase C J Endocrinol 1996 150: 129–140.

    Article  CAS  Google Scholar 

  23. Salem MA, Wolff GL . Potentiation of response to insulin and anti-insulin action by two human pituitary peptides in lean agouti A/a, obese yellow Avy/A, and C57BL/6J-ob/ob mice Soc Exp Biol Med 1989 191: 113–123.

    Article  CAS  Google Scholar 

  24. Watt PW, Finley E, Cork S, Clegg RA, Vernon RG . Chronic control of the beta- and alpha 2-adrenergic systems of sheep adipose tissue by growth hormone and insulin Biochem J 1991 273: 39–42.

    Article  CAS  Google Scholar 

  25. Slavin BG, Ong JM, Kern PA . Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes J Lipid Res 1994 35: 1535–1541.

    CAS  PubMed  Google Scholar 

  26. Doris R, Vernon RG, Houslay MD, Kilgour E . Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes Biochem J 1994 297: 41–45.

    Article  CAS  Google Scholar 

  27. Katsurada A, Iritani N, Fukuda H, Matsumura Y, Nishimoto N, Noguchi T, Tanaka T . Effects of nutrients and hormones on transcriptional and post-transcriptional regulation of acetyl-CoA carboxylase in rat liver Eur J Biochem 1990 190: 435–441.

    Article  CAS  Google Scholar 

  28. Napoli R, Cittadini A, Chow JC, Hirshman MF, Smith RJ, Douglas PS, Horton ES . Chronic growth hormone treatment in normal rats reduces post-prandial skeletal muscle plasma membrane GLUT1 content, but not glucose transport or GLUT4 expression and localization Biochem J 1996 315: 959–963.

    Article  CAS  Google Scholar 

  29. Adamafio NA, Kostyo JL, Cameron CM, Trimark JR, Dunbar JC . Acute effects of S-carboxymethylated human growth hormone on insulin resistance in the obese (ob/ob) mouse Metabolism 1988 37: 900–905.

    Article  CAS  Google Scholar 

  30. Ferrannini E . Insulin resistance versus insulin deficiency in NIDDM: problems & prospects Endocrine Rev 1998 19: 477–490.

    Article  CAS  Google Scholar 

  31. Lewis UJ, Lewis LJ, Salem MA, Staten NR, Galosy SS, Krivi GG . A recombinant-DNA-derived modification of human growth hormone (hGH44-191) with enhanced diabetogenic activity Cell Endocrinol 1991 78: (1–2): 45–54.

    Article  Google Scholar 

  32. Evans BA, Papaioannou M, Anastasopoulos F, Summers RJ . Differential regulation of beta3-adrenoceptors in gut and adipose tissue of genetically obese (ob/ob) C57BL/6J-mice Br J Pharmac 1998 124: 763–771.

    Article  CAS  Google Scholar 

  33. Hettiarachchi M, Watkinson A, Leung KC, Sinha YN, Ho KK, Kraegen EW . Human growth hormone fragment (hGH44-91) produces insulin resistance and hyperinsulinemia but is less potent than 22 kDa hGH in the rat Endocrine 1997 6: 47–52.

    Article  CAS  Google Scholar 

  34. Odagiri E, Sherrell BJ, Mount CD, Nicholson WE, Orth DN . Human placental immunoreactive corticotropin, lipotropin, and beta-endorphin: evidence for a common precursor Proc Natl Acad Sci, USA 1979 76: 2027–2031.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Thanks to Mr Anthony Civitarese for assistance with indirect calorimetry, and to Mr Ray Spark for plasma glucose analysis. This work was supported by Metabolic Pharmaceuticals.

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Correspondence to FM Ng.

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Heffernan, M., Thorburn, A., Fam, B. et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes 25, 1442–1449 (2001). https://doi.org/10.1038/sj.ijo.0801740

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Keywords

  • human growth hormone fragment
  • body weight
  • energy expenditure
  • lipolysis
  • growth hormone receptor

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