DHEA Administration Activates Transcription of Muscular Lipid Metabolic Enzymes via PPARα and PPARδ in Obese Rats

Abstract

Administration of dehydroepiandrosterone (DHEA), a precursor of sex steroid hormones, reduces total and visceral fat mass and elevates adipocytic adiponectin gene expression. The aim of this study is to investigate whether levels of peroxisome proliferator-activated receptors (PPARs) in muscle and transcription of PPAR target genes are affected by long-term DHEA administration or exercise training, and whether altered PPAR levels are associated with circulating adiponectin level in obese rats. After 14 weeks on a high-sucrose diet, obese male Wistar rats were assigned randomly to one of 3 groups: control, DHEA administration (1 mg/kg body weight), or exercise training (treadmill running for 1 h, 25 m/min, 5 days/week) for 6 weeks (n=7 for each group). Plasma DHEA and total adiponectin levels in the DHEA-treated and exercise-training groups were significantly higher than those in the obese control group. Additionally, DHEA administration and exercise training significantly increased muscular PPARα and PPARδ protein levels, with a concomitant increase in mRNA expression of 3β-hydroxyacyl-CoA dehydrogenase and cytochrome c oxidase IV, which are target genes of PPARα and PPARδ respectively. Moreover, DHEA administration increased these protein and mRNA levels to the same degree as exercise training. Circulating adiponectin level was positively correlated with plasma DHEA and with muscle levels of PPARα and PPARδ. These results suggest that in obese rats, secretion of adiponectin due to chronic DHEA administration and exercise training may contribute to an increase in the transcription of genes encoding lipid metabolic enzymes, mediated via elevated expression of PPARα and PPARδ in muscle.

Key words

dehydroepiandrosterone - skeletal muscle - peroxisome proliferator-activated receptor

• References

• 1 Houmard JA. Intramuscular lipid oxidation and obesity. Am J Physiol Regul Integr Comp Physiol 2008; 294: R1111-R1116
• 2 Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006; 116: 571-580
• 3 Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000; 20: 1868-1876
• 4 Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113: 159-170
• 5 De Pergola G, Giagulli VA, Garruti G, Cospite MR, Giorgino F, Cignarelli M, Giorgino R. Low dehydroepiandrosterone circulating levels in premenopausal obese women with very high body mass index. Metabolism 1991; 40: 187-190
• 6 Blanchette S, Marceau P, Biron S, Brochu G, Tchernof A. Circulating progesterone and obesity in men. Horm Metab Res 2006; 38: 330-335
• 7 Yamaguchi Y, Tanaka S, Yamakawa T, Kimura M, Ukawa K, Yamada Y, Ishihara M, Sekihara H. Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia. Clin Endocrinol 1998; 49: 377-383
• 8 Sato K, Iemitsu M, Aizawa K, Mesaki N, Fujita S. Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. Am J Physiol Endocrinol Metab 2011; 301: 274-280
• 9 Mohan PF, Ihnen JS, Levin BE, Cleary MP. Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity. J Nutr 1990; 120: 1103-1114
• 10 Hansen PA, Han DH, Nolte LA, Chen M, Holloszy JO. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol 1997; 273: R1704-R1708
• 11 Corona G, Rastrelli G, Giagulli VA, Sila A, Sforza A, Forti G, Mannucci E, Maggi M. Dehydroepiandrosterone supplementation in elderly men: a meta-analysis study of placebo-controlled trials. J Clin Endocrinol Metab 2013; 98: 3615-3626
• 12 Kimura M, Tanaka S, Yamada Y, Kiuchi Y, Yamakawa T, Sekihara H. Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. Endocrinology 1998; 139: 3249-3253
• 13 Karbowska J, Kochan Z. Effects of DHEA on metabolic and endocrine functions of adipose tissue. Horm Mol Biol Clin Investig 2013; 14: 65-74
• 14 Karbowska J, Kochan Z. Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma. Biochem Pharmacol 2005; 70: 249-257
• 15 Pérez-de-Heredia F, Sánchez J, Priego T, Nicolás F, Portillo Mdel P, Palou A, Zamora S, Garaulet M. Adiponectin is involved in the protective effect of DHEA against metabolic risk in aged rats. Steroids 2008; 73: 1128-1136
• 16 Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S, Kadowaki T. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013; 503: 493-499
• 17 Barnea M, Madar Z, Froy O. High-fat diet followed by fasting disrupts circadian expression of adiponectin signaling pathway in muscle and adipose tissue. Obesity 2010; 18: 230-238
• 18 Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 2006; 55: 2562-2570
• 19 Yokokawa T, Sato K, Iwanaka N, Honda H, Higashida K, Iemitsu M, Hayashi T, Hashimoto T. Dehydroepiandrosterone activates AMP kinase and regulates GLUT4 and PGC-1α expression in C2C12 myotubes. Biochem Biophys Res Commun 2015; 463: 42-47
• 20 Jeong S, Yoon M. Swimming’s prevention of ovariectomy-induced obesity through activation of skeletal-muscle PPARα. Int J Sport Nutr Exerc Metab 2012; 22: 1-10
• 21 Rector RS, Uptergrove GM, Borengasser SJ, Mikus CR, Morris EM, Naples SP, Laye MJ, Laughlin MH, Booth FW, Ibdah JA, Thyfault JP. Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats. Am J Physiol Endocrinol Metab 2010; 298: E1179-E1187
• 22 Chicco A, D’Alessandro ME, Karabatas L, Pastorale C, Basabe JC, Lombardo YB. Muscle lipid metabolism and insulin secretion are altered in insulin-resistant rats fed a high sucrose diet. J Nutr. 2003; 133: 127-133
• 23 Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, Yamaguchi I. Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol 2002; 283: H1750-H1760
• 24 Aizawa K, Iemitsu M, Otsuki T, Maeda S, Miyauchi T, Mesaki N. Sex differences in steroidogenesis in skeletal muscle following a single bout of exercise in rats. J Appl Physiol 2008; 104: 67-74
• 25 Watanabe S, Sato K, Hasegawa N, Kurihara T, Matsutani K, Sanada K, Hamaoka T, Fujita S, Iemitsu M. Serum C1q as a novel biomarker of sarcopenia in older adults. FASEB J 2015; 29: 1003-1010
• 26 Miyazaki S, Izawa T, Ogasawara JE, Sakurai T, Nomura S, Kizaki T, Ohno H, Komabayashi T. Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectin. Life Sci 2010; 86: 691-698
• 27 Bruun JM, Helge JW, Richelsen B, Stallknecht B. Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 2006; 290: E961-E967
• 28 Ryu JW, Kim MS, Kim CH, Song KH, Park JY, Lee JD, Kim JB, Lee KU. DHEA administration increases brown fat uncoupling protein 1 levels in obese OLETF rats. Biochem Biophys Res Commun 2003; 303: 726-731
• 29 Kochan Z, Karbowska J. Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. Mol Cell Endocrinol 2004; 218: 57-64
• 30 Usui T, Kajita K, Kajita T, Mori I, Hanamoto T, Ikeda T, Okada H, Taguchi K, Kitada Y, Morita H, Sasaki T, Kitamura T, Sato T, Kojima I, Ishizuka T. Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice. FEBS Lett 2014; 588: 1935-1941
• 31 Aizawa K, Iemitsu M, Maeda S, Jesmin S, Otsuki T, Mowa CN, Miyauchi T, Mesaki N. Expression of steroidogenic enzymes and synthesis of sex steroid hormones from DHEA in skeletal muscle of rats. Am J Physiol Endocrinol Metab 2007; 292: E577-E584
• 32 Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab 2012; 9: 47