Horm Metab Res 2013; 45(01): 31-37
DOI: 10.1055/s-0032-1321879
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Effects of Adrenomedullin on Tumour Necrosis Factor Alpha, Interleukins, Endothelin-1, Leptin, and Adiponectin in the Epididymal Fat and Soleus Muscle of the Rat

S. B. Liao
1   Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
2   Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
,
P. F. Wong
2   Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
,
W. S. O,
B. M. Y. Cheung
4   Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
5   Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
,
F. Tang
2   Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
5   Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
› Author Affiliations
Further Information

Publication History

received 12 April 2012

accepted 09 July 2012

Publication Date:
06 September 2012 (online)

Abstract

Adrenomedullin (ADM) is a peptide hormone, which participates in the development of metabolic syndrome. In this study, we have investigated the interaction of ADM and cytokines, endothelin-1 (EDN-1) and adipokines in the epididymal fat and the soleus muscle. Epididymal fat and soleus muscles from adult male Sprague-Dawley rat were incubated with ADM at concentration of 100 nM for the study of the gene expression and secretion of tumour necrosis factor (TNF-α), EDN-1, leptin, adiponectin, interleukin 1β (IL-1β), and IL-6. The effects of TNF-α and EDN-1 on ADM gene expression and secretion were also investigated. The results showed that ADM decreased the gene expression and protein secretion of TNF-α in both the epididymal fat and the soleus muscle and decreased IL-1β gene expression and secretion in the soleus muscle. It also decreased endothelin gene expression and adiponectin gene expression and release and increased IL-6 and leptin gene expression and secretion in the epididymal fat. These effects were effectively blocked by the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP8–37, but not by the ADM receptor antagonist, hADM22–52. The reduction of inflammatory cytokines and EDN-1 may help to decrease insulin resistance and increase glucose uptake. As TNF-α also increases ADM levels in the epididymal fat and the soleus muscle and EDN-1 also increases ADM levels in the epididymal fat, they may form a feedback loop with ADM in these tissues. The increase in leptin and the decrease in adiponectin by ADM in the epididymal fat may have opposite effects on metabolism.

 
  • References

  • 1 Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010; 289645-289655
  • 2 Xu H, Barnes GT, Yang Q, Tan G, Yang DS, 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
  • 3 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL Ferrante Jr Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
  • 4 Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-1033
  • 5 Fernández-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr rev 2003; 24: 278-301
  • 6 Ferri C, Bellini C, Desideri G, Baldoncini R, Properzi G, Santucci A, De Mattia G. Circulating endothelin-1 levels in obese patients with the metabolic syndrome. Exp Clin Endocrinol Diabetes 1997; 105: 38-40
  • 7 Migdalis IN, Kalogeropoulou K, Iliopoulou V, Triantafilou P, Charalabides J, Mortzos G, Cordopatis C. Plasma levels of endothelin, lipid peroxides and prostacyclin in diabetic patients with macroangiopathy. Diabetes Res Clin Pract 2001; 54: 129-136
  • 8 Weil BR, Westby CM, Vanguilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Enhanced endothelin-1 system activity with overweight and obesity. AM J Physiol Heart Circ Physiol 2011; 301: H689-H695
  • 9 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kiumura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288-1295
  • 10 Ceddia Jr RB, WNW Curi R. Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. Int J Obes 1999; 23: 75-82
  • 11 Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52: 812-817
  • 12 Cheung BMY, Hwang ISS, Li CY, W. S. O. Tsang KW, Liang RY, Kumana CR, Tang F. Increased adrenomedullin expression in lungs in endotoxaemia. J Endocrinol 2004; 181: 339-345
  • 13 Li YY, Cheung BM, Wong LY, Hwang ISS, Kumana CR, Tang F. Adrenomedullin gene expression and levels in the cardiovascular system after treatment with lipopolysaccharide. Neuropeptides 2005; 39: 73-80
  • 14 Li YY, Wong YF, Cheung BMY, Hwang ISS, Tang F. Differential induction of adrenomedullin, interleukins and tumour necrosis factor-α by lipopolysaccharaide in rat tissues in vivo. Clin Exp Pharmacol Physiol 2005; 32: 110-118
  • 15 Hwang IS, Tang F, Leung PP, Li YY, Fan ST, Luk KM. The gene expression of adrenomedullin, calcitonin-receptor-like receptor and receptor activity modifying proteins (RAMPS) in CCl (4)-induced rat liver cirrhosis. Reg Pept 2006; 135: 69-77
  • 16 Wong LYF, Cheung BMY, Li YY, Tang F. Adrenomedullin is both proinflammatory and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line. Endocriology 2005; 146: 1321-1327
  • 17 Liao SB, Kong LHM, Tang F. W. S. O. Possible functions of adrenomedullin from the seminal fluid in the female reproductive tracts of the rat. Syst Biol Reprod Med 2012; June 18 [Epub ahead of print]
  • 18 Nomura I, Kato J, Tokashiki M, Kitamura K. Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity. Regul Pept 2009; 158: 127-131
  • 19 Hayashi M, Shimosawa T, Isaka M, Yamada S, Fujita T. Plasma adrenoemdullin in diabetes. Lancet 1997; 350: 1449-1450
  • 20 Xu A, Yin S, Wong L, Chan KW, Lam KS. Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice. Endocrinology 2004; 145: 487-494
  • 21 Moller DE. Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000; 11: 212-217
  • 22 Borst SE. The role of TNF-alpha in insulin resistance. Endocrine 2004; 23: 177-182
  • 23 De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE. Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am J Physiol Endocrinol Metab 2007; 293: E713-E725
  • 24 Irving RJ, Noon JP, Watt GC, Webb DJ, Walker BR. Activation of the endothelin system in insulin resistance. QJM 2001; 94: 321-326
  • 25 Wollesen F, Berglund L, Berne C. Plasma endothelin-1 and total insulin exposure in diabetes mellitus. Clin Sci (Lond) 1999; 97: 149-156
  • 26 Isumi Y, Minamino N, Kubo A, Nishimoto N, Yoshizaki K, Yoshioka M, Kangawa K, Matsuo H. Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells. Biochem Biophys Res Commun 1998; 17: 325-331
  • 27 Isumi Y, Kubo A, Katafuchi T, Kangawa K, Minamino N. Adrenomedullin suppresses interleukin-1β-induced tumor necrosis factor-α production in Swiss 3T3 cells. FEBS Lett 1999; 463: 110-114
  • 28 Hay DL, Conner AC, Howitt SG, Smith DM, Poyner DR. The pharmacology of adrenomedullin receptors and their relationship to CGRP receptors. J Mol Neurosci 2004; 22: 105-113
  • 29 Tomoda Y, Kikumoto K, Isumi Y, Katafuchi T, Tanaka A, Kangawa K, Dohi K, Minamino N. Cardiac fibroblasts are major production and target cells of adrenomedullin in the heart in vitro. Cardiovaso Res 2001; 49: 721-730
  • 30 Di Santo E, Alonzi T, Poli V, Fattori E, Toniatt C, Sironi M, Ricciardi-Castagnoli P, Ghezzi P. Differential effects of IL-6 on systemic and central production of TNF: a study with IL-6 deficient mice. Cytokine 1997; 9: 300-306
  • 31 Lee YC, Juan CC, Fang VS, Hsu YP, Lin SH, Kwok CF, Ho LT. Evidence that endothelin-1 (ET-1) inhibits insulin-stimulated glucose uptake in rat adipocytes mainly through ETA receptors. Metabolism 1998; 47: 1468-1471
  • 32 Iemura-Inaba C, Nishikimi T, Akimoto K, Yoshihara F, Minamino N, Matsuoka H. Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes. Am J Physiol 2008; 295: R1376-R1384
  • 33 Ahima RS, Osei SY. Adipokines in obesity. Front Horm Res 2008; 36: 182-197
  • 34 Trujullo ME, Lee MJ, Sullivan S, Feng J, Schneider SH, Greenberg AS, Fried SK. Tumor necrosis factor α and glucocorticoid synergistically increase leptin production in human adipose tissue: role for p38 mitogen-activated protein kinase. J Clin Endcoinol Metab 2006; 91: 1484-1490
  • 35 Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003; 285: E527-E533
  • 36 Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X, Janson PA, Smith U. High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator. Obes Res 2004; 12: 454-460
  • 37 Li Y, Totsune K, Takeda K, Furuyama K, Shibahara S, Takahashi K. Differential expression of adrenomedullin and resistin in 3T3-L1 adipocytes treated with tumor necrosis factor-α. Eur J Endocrinol 2003; 149: 231-238
  • 38 Youd JM, Rattigan S, Clark MG. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes 2000; 48: 1904-1909
  • 39 Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 1996; 97Z: 1111-1116
  • 40 Sutherland JP, McKinley B, Eckel RH. The metabolic syndrome and inflammation. Metab Syndr Relat Disord 2004; 2: 82-104
  • 41 Shimosawa T, Ogihara T, Matsui H, Asano T, Ando K, Fujita T. Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress. Hypertension 2003; 41: 1080-1085
  • 42 Zhang J, Zhang BH, Yu YR, Tang CS, Qi YF. Adrenomedullin protects against fructose-induced insulin resistance and myocardial hypertrophy in the rat. Peptides 2011; 32: 1425-1421
  • 43 Ong KL, Tso AW, Leung RY, Cherny SS, Sham PC, Lam TH, Cheung BM, Lam KS. A genetic variant in the gene encoding adrenomedullin predicts the development of dysglycemia over 6.4 years in Chinese. Clin Chim Acta 2011; 412: 353-357