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DOI: 10.1055/s-0034-1381998
Growth Hormone Ameliorates Adipose Dysfunction During Oxidative Stress and Inflammation and Improves Glucose Tolerance in Obese Mice
Publication History
received 10 October 2013
accepted 13 May 2014
Publication Date:
04 July 2014 (online)
Abstract
Patients with adult growth hormone deficiency exhibit visceral fat accumulation, which gives rise to a cluster of metabolic disorders such as impaired glucose tolerance and dyslipidemia. Plasma growth hormone levels are lower in obese patients with metabolic syndrome than in healthy subjects. Here we examined the hypothesis that exogenous growth hormone administration regulates function of adipose tissue to improve glucose tolerance in diet-induced obese mice. Twelve-week-old obese male C57BL/6 J mice received bovine growth hormone daily for 6 weeks. In epididymal fat, growth hormone treatment antagonized diet-induced changes in the gene expression of adiponectin, leptin, and monocyte chemoattractant protein-1, and significantly increased the gene expression of interleukin-10 and CD206. Growth hormone also suppressed the accumulation of oxidative stress marker, thiobarbituric acid-reactive substances, in the epididymal fat and enhanced the gene expression of anti-oxidant enzymes. Moreover, growth hormone significantly restored glucose tolerance in obese mice. In cultured 3T3-L1 adipocytes, growth hormone prevented the decline in adiponectin gene expression in the presence of hydrogen peroxide. These results suggest that growth hormone administration ameliorates glucose intolerance in obese mice presumably by decreasing adipose mass, oxidative stress, and chronic inflammation in the visceral fat.
Key words
growth hormone - adipose tissue - oxidative stress - inflammation - adiponectin - glucose toleranceSupporting Information
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References
- 1 Beshyah SA, Freemantle C, Thomas E, Rutherford O, Page B, Murphy M, Johnston DG. Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults. Clin Endocrinol (Oxf) 1995; 42: 179-189
- 2 Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorne M. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998; 83: 382-395
- 3 Attanasio AF, Bates PC, Ho KK, Webb SM, Ross RJ, Strasburger CJ, Bouillon R, Crowe B, Selander K, Valle D, Lamberts SW. Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status – 3-year results from the HypoCCS Database. J Clin Endocrinol Metab 2002; 87: 1600-1606
- 4 Hoffman AR, Kuntze JE, Baptista J, Baum HB, Baumann GP, Biller BM, Clark RV, Cook D, Inzucchi SE, Kleinberg D, Klibanski A, Phillips LS, Ridgway EC, Robbins RJ, Schlechte J, Sharma M, Thorner MO, Vance ML. Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004; 89: 2048-2056
- 5 Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb 2011; 18: 629-639
- 6 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548-2556
- 7 Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P. Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond) 2006; 110: 267-278
- 8 Friedman JM. Obesity: Causes and control of excess body fat. Nature 2009; 459: 340-342
- 9 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867
- 10 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
- 11 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003; 112: 1785-1788
- 12 Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15: 2792-2800
- 13 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
- 14 Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003; 52: 1655-1663
- 15 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50: 2094-2099
- 16 Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, Igura T, Maeda N, Kihara S, Funahashi T, Matsuzawa Y, Shimomura I, Hayashi N. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 2007; 47: 556-564
- 17 Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol 2008; 154: 557-568
- 18 Ding J, List EO, Bower BD, Kopchick JJ. Differential effects of growth hormone versus insulin-like growth factor-I on the mouse plasma proteome. Endocrinology 2011; 152: 3791-3802
- 19 Bielohuby M, Schaab M, Kummann M, Sawitzky M, Gebhardt R, Binder G, Frystyk J, Bjerre M, Hoeflich A, Kratzsch J, Bidlingmaier M. Serum IGF-I is not a reliable pharmacodynamic marker of exogenous growth hormone activity in mice. Endocrinology 2011; 152: 4764-4776
- 20 Lubbers ER, List EO, Jara A, Sackman-Sala L, Cordoba-Chacon J, Gahete MD, Kineman RD, Boparai R, Bartke A, Kopchick JJ, Berryman DE. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity?. J Endocrinol 2013; 216: 363-374
- 21 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830
- 22 Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505
- 23 Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 2009; 58: 2574-2582
- 24 Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 2004; 109: 2046-2049
- 25 Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Pedersen AA, Kalthoff C, Tullin S, Sams A, Summer R, Walsh K. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 2010; 285: 6153-6160
- 26 Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett 2006; 580: 2917-2921
- 27 Wu Y, Liu C, Sun H, Vijayakumar A, Giglou PR, Qiao R, Oppenheimer J, Yakar S, LeRoith D. Growth hormone receptor regulates beta cell hyperplasia and glucose-stimulated insulin secretion in obese mice. J Clin Invest 2011; 121: 2422-2426
- 28 Vilar L, Naves LA, Costa SS, Abdalla LF, Coelho CE, Casulari LA. Increase of classic and nonclassic cardiovascular risk factors in patients with acromegaly. Endocr Pract 2007; 13: 363-372
- 29 Colao A, Spinelli L, Cuocolo A, Spiezia S, Pivonello R, di Somma C, Bonaduce D, Salvatore M, Lombardi G. Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab 2002; 87: 3097-3104
- 30 Frick F, Bohlooly-Y M, Lindén D, Olsson B, Törnell J, Edén S, Oscarsson J. Long-term growth hormone excess induces marked alterations in lipoprotein metabolism in mice. Am J Physiol Endocrinol Metab 2001; 281: E1230-E1239
- 31 Olsson B, Bohlooly-Y M, Fitzgerald SM, Frick F, Ljungberg A, Ahrén B, Törnell J, Bergström G, Oscarsson J. Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet. Endocrinology 2005; 146: 920-930
- 32 Møller N, Jørgensen JO, Schmitz O, Møller J, Christiansen J, Alberti KG, Orskov H. Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am J Physiol 1990; 258: E86-E91
- 33 Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, Lam KS, Xu A. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 2011; 286: 34559-34566
- 34 List EO, Palmer AJ, Berryman DE, Bower B, Kelder B, Kopchick JJ. Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes. Diabetologia 2009; 52: 1647-1655
- 35 Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009; 15: 1082-1087