Download PDF
Horm Metab Res 2004; 36(9): 607-613
DOI: 10.1055/s-2004-825905
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Effects of Growth Hormone (GH) on mRNA Levels of Uncoupling Proteins 1, 2, and 3 in Brown and White Adipose Tissues and Skeletal Muscle in Obese Mice

C.  Hioki1, 3 , T.  Yoshida1 , A.  Kogure1 , Y.  Takakura1 , T.  Umekawa1 , K.  Yoshioka1 , A.  Shimatsu3 , T.  Yoshikawa2
  • 1Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
  • 2Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
  • 3Clinical Research Institute for Endocrine and Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, Japan
Further Information

Publication History

Received 28 October 2003

Accepted after revision 20 April 2004

Publication Date:
05 October 2004 (online)

Also available at
    Permissions and Reprints

Abstract

We have investigated whether GH treatment influences the expression of UCP1, 2 and 3 mRNA in a KK-Ay obese mouse model. KK-Ay mice (n = 10) and C57Bl/6J control mice (n = 10) were injected subcutaneously with human GH (1.0 mg/kg/day and 3.5 mg/kg/day) for 10 days, and compared with mice injected with physical saline. The KK-Ay obese mice weighed significantly less (p < 0.01 : 1.0 mg/kg/day, p < 0.05 : 3.5 mg/kg/day) and had smaller inguinal subcutaneous and perimetric white adipose tissue (WAT) pads (p < 0.05 : 3.5 mg/kg/day), but increased skeletal muscle weight (p < 0.05). The brown adipose tissue (BAT) weight did not change significantly. Not only plasma free fatty acid and glucose levels but also plasma insulin levels decreased. The reduced HOMA-IR (homeostasis model assessment-insulin resistance) values suggested that insulin resistance was improved by GH treatment. UCP1 mRNA levels increased after the 3.5 mg GH treatment by 2.8-fold (p < 0.01 vs. saline controls) and 2.0-fold (p < 0.05 vs. 1 mg GH treatment) in BAT, and by 6.0-fold in subcutaneous WAT (p < 0.05 vs. controls). UCP2 mRNA levels increased 2.2-fold (p < 0.05 vs. control) and 2.1-fold (p < 0.05 vs. 1 mg GH treatment) in BAT, and 2.0-fold (p < 0.05 vs. controls) in skeletal muscle. One mg GH administration also stimulated UCP1 mRNA expression by 2.5-fold (p < 0.05 vs. controls) and UCP3 mRNA expression by 2.8-fold (p < 0.05 vs. controls) in the muscle. On the other hand, lean mice showed no significant difference in body composition or plasma parameters. UCP1, 2 and 3 mRNA expression in lean mice did not show any significant change after treatment with GH. We conclude that GH treatment increased mRNA levels for not only UCP1, but also UCP 2 and 3 in BAT, WAT and muscle in a KK-Ay obese mouse model. These findings suggest that GH-induced thermogenesis may contribute to the reduction in WAT and energy expenditure.

Key words

Growth hormone · Adipose tissues · Skeletal muscle · Uncoupling proteins · Thermogenesis · Insulin resistance

References

  • 1 Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies.  FASEB J. 1990;  4 2890-2898
    PubMedGoogle Scholar
  • 2 Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J. Only UCP1 can mediate adaptive non-shivering thermogenesis in the cold.  FASEB J. 2001;  15 2048-2050
    PubMedGoogle Scholar
  • 3 Yoshida T, Umekawa T, Kumamoto K, Sakane N, Kogure A, Kondo M, Wakabayashi Y, Kewada T, Nagase I, Saito M. β3-adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers.  Am J Physiol. 1998;  274 E469-E475
    PubMedGoogle Scholar
  • 4 Yoshida T, Sakane N, Umekawa T, Kogure A, Kondo M, Kumamoto K, Kawada T, Nagase I, Saito M. Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice.  Int J Obes Relat Metab Disord. 1999;  6 570-575
    PubMedGoogle Scholar
  • 5 Boss O, Samec S, Paoloni-Giacobino A. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression.  FEBS Lett. 1997;  408 39-42
    CrossrefPubMedGoogle Scholar
  • 6 Vidal-Puing A, Solanes G, Grujic D, Flier J S, Lowell B B. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue.  Biochem Biophys Res Commun. 1997;  235 79-82
    CrossrefPubMedGoogle Scholar
  • 7 Richelsen B. Action of growth hormone in adipose tissue.  Horm Res. 1997;  48 105-110
    PubMedGoogle Scholar
  • 8 Ridderstrale M, Tornqvist H. Effects of tyrosine kinase inhibitors on tyrosine phosphorylations and the insulin-like effects in response to human growth hormone in isolated rat adipocytes.  J Endocrinol. 1996;  137 4650-4656
    PubMedGoogle Scholar
  • 9 Johansen T, Richelsen B, Hansen H S, Din N, Malmlof K. Growth hormone-mediated breakdown of body fat: Effects of GH on lipases in adipose tissue and skeletal muscle of old rats fed different diets.  Horm Metab Res. 2003;  35 243-250
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, Tumour Necrosis Factor alpha, Growth Hormone, and IL-6 in 3T3-L1 adiposytes.  Horm Metab Res. 2003;  35 147-152
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Takahashi N, Patel H R, Qi Y, Dushay J, Ashima R S. Divergent effects of leptin in mice susceptible or resistant to obesity.  Horm Metab Res. 2002;  34 691-697
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Nagasawa A, Fukui K, Funahashi T, Maeda N, Shimomura I, Kihara S, Waki M, Takamatsu K, Matsuzawa Y. Effects of Soy protein diet on the expression of adipose genes and plasma adiponectin.  Horm Metab Res. 2002;  34 635-639
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Khalfallah Y, Sassolas G, Borson-Chazot F, Vega N, Vidal H. Expression of insulin target genes in skeletal muscles and adipose tissue in adult patients with growth hormone deficiency: effect of one-year recombinant human growth hormone therapy.  J Endocrinol. 2001;  171 285-292
    CrossrefPubMedGoogle Scholar
  • 14 Iwatsuka H, Shino A, Suzuoka Z iro. General survey of diabetic features of yellow KK mice.  Endocrinol Jpn. 1970;  17 23-35
    CrossrefPubMedGoogle Scholar
  • 15 Scacchi M, Pincelli A I, Cavafnini F. Growth hormone in obesity.  Int J Obes Relat Metab Disord. 1999;  23 260-271
    CrossrefPubMedGoogle Scholar
  • 16 Clark R, Mortensen D, Carlsson L, Carlsson B, Carmignac D, Robinson I. The obese growth hormone (GH)-deficient dwarf rat: body fat responses to patterned deliver of GH and insulin-like growth factor-1.  Endocrinology. 1996;  137 1904-1912
    CrossrefPubMedGoogle Scholar
  • 17 Kindblom J M, Gothe S, Forrest D, Törnell J, Vennstrom B, Ohlsson C. GH substitution reverses the growth phenotype but not the defective ossification in thyroid hormone in thyroid hormone receptor α1-/- β-/-mice.  J Endocrinol. 2001;  171 15-22
    CrossrefPubMedGoogle Scholar
  • 18 Champigny O, Ricquier D, Blondel O, Mayers R M, Briscoe MG, Holloway B R. β3- adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial in coupling protein in adult dogs.  Proc Natl Acad Sci USA. 1991;  88 10774-10777
    PubMedGoogle Scholar
  • 19 Nagase I, Yoshida T, Kumamoto K, Umekawa T, Sakane N, Nikami H, Kawada T, Saito M. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic β3-adrenergic agonist.  J Clin Invest. 1996;  12 2898-2904
    PubMedGoogle Scholar
  • 20 Yoshitomi H, Yamazaki K, Abe S, Tanaka I. Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue and skeletal muscle in chronic β3-adrenergic receptor agonist treatment.  Biochem and Biophysical Research communications. 1998;  253 85-91
    PubMedGoogle Scholar
  • 21 Donaldson D L, Hollowell J G, Pan F P, Gifford R A, Moore W V. Growth hormone secretory profiles: Variation on consecutive nights.  J Pediatr. 1989;  115 51-56
    PubMedGoogle Scholar
  • 22 Weigle D S, Selfridge L E, Schwartz M W, Seeley R J, Cummings D E, Havel P J, Kuijper J L, Beltran-del R io . Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential for the effect of fasting.  Diabetes. 1998;  47 298-302
    PubMedGoogle Scholar
  • 23 Boss O, Samec S, Desplanches D, Mayet M H, Seydoux J, Muzzin P, Giacobino J P. Effect of endurance training on mRNA expression of uncoupling proteins 1, 2, and 3 in the rat.  FASEB J. 1998;  12 335-339
    PubMedGoogle Scholar
  • 24 Samec S, Seydoux J, Dullo A G. Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate?.  FASEB J. 1998;  12 715-724
    PubMedGoogle Scholar
  • 25 Pedersen S B, Kristensen K, Fisker S, Otto J, Jørgensen L, Christiansen J S, Richelsen B. Regulation of uncoupling protein-2 and -3 by growth hormone in skeletal muscle and adipose tissue in growth hormone-deficient adults.  J Clin Endoclinol Metab. 1999;  84 4073-4078
    CrossrefPubMedGoogle Scholar
  • 26 Schrauwen P, Xia J, Bogardus C, Pratley R E, Ravussin E. Skeletal muscle uncoupling protein 3 expression is a determinant of energy expenditure in Pima Indians.  Diabetes. 1999;  48 146-149
    PubMedGoogle Scholar
  • 27 Larkin S, Mull E, Miao W, Pittner R, Albrandt K, Moore C, Young A, Denaro M, Beaumont K, Moore C, Young A, Denaro M, Beaumont K. Regulation of the third member of the uncoupling protein family, UCP3, by cold and thyroid hormone.  Biochem Biophys Res Commun. 1997;  240 222-227
    CrossrefPubMedGoogle Scholar
  • 28 Wolthers T, Groftne T, Moller N, Christiansen J S, Orskov H, Weeke J, Jørgensen J O. Calorigenic effects of growth hormone: the role of thyroid hormones.  J Clin Endocrinol Metab.. 1996;  81 1416-1419
    CrossrefPubMedGoogle Scholar
  • 29 Witter M, Fluck M, Hoppeler H, Muller S, Desplanches D, Billeter R. Prolonged unloading of rat soleus muscle causes distinct adaptations of the gene profile.  FASEB J. 2002;  16 884-886
    PubMedGoogle Scholar
  • 30 Beshyah S A, Henderson A, Niththyananthan R, Skinner E, Anyaoku V, Richmond W, Sharp P, Johnston D G. The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance.  J Clin Endocrinol Metab. 1995;  80 356-363
    CrossrefPubMedGoogle Scholar
  • 31 Bulow B, Agardh C D, Eckert B, Erfurth E M. Individualized low-dose growth hormone (GH) treatment in GH-deficient adults with childhood-onset disease: metabolic effects during fasting and hypoglycemia.  Metabolism. 1999;  48 1003-1010
    CrossrefPubMedGoogle Scholar

C. Hioki

Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

465-Kajii-cho · Kawaramachi-Hirokoji · Kamikyo-ku · Kyoto 602-8566 · Japan

Phone: +81 (75) 2515506

Fax: +81 (75) 2523721

Email: chioki@koto.kpu-m.ac.jp

      >