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Exp Clin Endocrinol Diabetes 2015; 123(02): 80-87
DOI: 10.1055/s-0034-1398502
Article
© Georg Thieme Verlag KG Stuttgart · New York

Impact of Toll-like-receptor-9 (TLR9) Deficiency on Visceral Adipose Tissue Adipokine Expression during Chronic DSS-induced Colitis in Mice

T. Karrasch
1   Department of Internal Medicine III, Giessen University Hospital, Germany
,
A. Schmid
1   Department of Internal Medicine III, Giessen University Hospital, Germany
,
A. Kopp
2   Department of Internal Medicine I, Regensburg University Hospital, Germany
,
F. Obermeier
2   Department of Internal Medicine I, Regensburg University Hospital, Germany
,
C. Hofmann
2   Department of Internal Medicine I, Regensburg University Hospital, Germany
,
A. Schäffler
1   Department of Internal Medicine III, Giessen University Hospital, Germany
› Author Affiliations
Further Information

Publication History

received 12 August 2014
first decision 27 November 2014

accepted 17 December 2014

Publication Date:
05 February 2015 (online)

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Abstract

Background: Studies postulate an involvement of adipokines in inflammatory gastrointestinal diseases. Leptin-deficient ob/ob mice as well as TLR9-deficient mice have a more moderate course of chronic DSS-induced colitis (DSS-CC) and adipocytes do express functional TLR9 molecules.

Material and Methods: Adipokine mRNA expression in visceral adipose tissue of mice before and after the induction of DSS-CC was investigated. Experiments were performed in both TLR9wt/wt and TLR9-/- mice. In vitro, the effect of TLR9 blocking peptide on leptin and visfatin protein secretion was studied in 3T3-L1 adipocytes.

Results: Induction of DSS-CC led to an upregulation of leptin mRNA expression in TLR9wt/wt mice, while TLR9-/- animals showed a significant reduction of leptin expression even below baseline. While visfatin expression remained unchanged in TLR9wt/wt animals, TLR9-/- mice exhibited a significant induction during DSS-CC. CTRP-3 expression was reduced after colitis induction only in TLR9-/- animals. Of note, IL-6 expression levels remained unchanged, while CXCL1/KC and cyclophilin A expression was reduced in DSS-CC. Inhibition of TLR9 signaling by using TLR9 blocking peptide led to reduced leptin protein secretion into cell culture supernatants in 3T3-L1 adipocytes, while visfatin protein secretion was enhanced.

Conclusions: DSS-CC leads to differential adipokine expression profiles in the visceral fat pad in TLR9wt/wt vs. TLR9-/- mice. In vitro, inhibition of TLR9 signaling induces visfatin secretion while inhibiting leptin secretion in adipocytes. Thus, visceral adipokines are regulated by intact TLR9 signaling pathway and a specific interplay between the leptin- and the TLR9-pathways might be of pathophysiological importance in chronic intestinal inflammation.

Key words

leptin - visfatin - CTRP-3 - IL-6 - visceral adipose tissue - TLR9 - DSS - chronic colitis
 

  • References

  • 1 Al-Suhaimi EA, Shehzad A. Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity. Eur J Med Res 2013; 18: 12 DOI: 10.1186/2047-783X-18-12.
    CrossrefPubMedGoogle Scholar
  • 2 Siegmund B, Lehr HA, Fantuzzi G. Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 2002; 122: 2011-2025
    CrossrefPubMedGoogle Scholar
  • 3 Okayasu I, Hatakeyama S, Yamada M et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 1990; 98: 694-702
    PubMedGoogle Scholar
  • 4 Obermeier F, Dunger N, Strauch UG et al. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 2005; 129: 913-927 DOI: 10.1053/j.gastro.2005.06.061.
    CrossrefPubMedGoogle Scholar
  • 5 Desreumaux P, Ernst O, Geboes K et al. Inflammatory alterations in mesenteric adipose tissue in Crohn's disease. Gastroenterology 1999; 117: 73-81
    CrossrefPubMedGoogle Scholar
  • 6 Karmiris K, Koutroubakis IE, Xidakis C et al. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm Bowel Dis 2006; 12: 100-105
    CrossrefPubMedGoogle Scholar
  • 7 Paul G, Schaffler A, Neumeier M et al. Profiling adipocytokine secretion from creeping fat in Crohn's disease. Inflamm Bowel Dis 2006; 12: 471-477
    CrossrefPubMedGoogle Scholar
  • 8 Hofmann C, Chen N, Obermeier F et al. C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts. Inflamm Bowel Dis 2011; 17: 2462-2471 DOI: 10.1002/ibd.21647.
    CrossrefPubMedGoogle Scholar
  • 9 Weigert J, Obermeier F, Neumeier M et al. Circulating levels of chemerin and adiponectin are higher in ulcerative colitis and chemerin is elevated in Crohn's disease. Inflamm Bowel Dis 2010; 16: 630-637 DOI: 10.1002/ibd.21091.
    CrossrefPubMedGoogle Scholar
  • 10 Schaffler A, Furst A, Buchler C et al. Vascular endothelial growth factor secretion from mesenteric adipose tissue and from creeping fat in Crohn's disease. Journal of Gastroenterology and Hepatology 2006; 21: 1419-1423 DOI: 10.1111/j.1440-1746.2006.04301.x.
    PubMedGoogle Scholar
  • 11 Schaffler A, Furst A, Buchler C et al. Secretion of RANTES (CCL5) and interleukin-10 from mesenteric adipose tissue and from creeping fat in Crohn's disease: regulation by steroid treatment. Journal of Gastroenterology and Hepatology 2006; 21: 1412-1418 DOI: 10.1111/j.1440-1746.2006.04300.x.
    PubMedGoogle Scholar
  • 12 Schaffler A, Hamer OW, Dickopf J et al. Admission visfatin levels predict pancreatic and peripancreatic necrosis in acute pancreatitis and correlate with clinical severity. The American journal of gastroenterology 2011; 106: 957-967 DOI: 10.1038/ajg.2010.503.
    CrossrefPubMedGoogle Scholar
  • 13 Schaffler A, Hamer O, Dickopf J et al. Admission resistin levels predict peripancreatic necrosis and clinical severity in acute pancreatitis. The American journal of gastroenterology 2010; 105: 2474-2484 DOI: 10.1038/ajg.2010.278.
    CrossrefPubMedGoogle Scholar
  • 14 Schaffler A, Landfried K, Volk M et al. Potential of adipocytokines in predicting peripancreatic necrosis and severity in acute pancreatitis: pilot study. Journal of Gastroenterology and Hepatology 2007; 22: 326-334 DOI: 10.1111/j.1440-1746.2006.04364.x.
    CrossrefPubMedGoogle Scholar
  • 15 Schäffler A, Herfarth H. Creeping fat in Crohn´s disease: travelling in a creeper lane of research?. Gut 2005; 54: 742-744
    CrossrefPubMedGoogle Scholar
  • 16 Fink C, Karagiannides I, Bakirtzi K et al. Adipose tissue and inflammatory bowel disease pathogenesis. Inflamm Bowel Dis 2012; 18: 1550-1557 DOI: 10.1002/ibd.22893.
    CrossrefPubMedGoogle Scholar
  • 17 Schäffler A, Schölmerich J, Büchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue – emerging role in intestinal and mesenteric diseases. Nature Clinical Practice (Gastroenterology and Hepatology) 2005; 2: 103-111
    PubMedGoogle Scholar
  • 18 Schaffler A, Scholmerich J. The role of adiponectin in inflammatory gastrointestinal diseases. Gut 2009; 58: 317-322 DOI: 10.1136/gut.2008.159210.
    CrossrefPubMedGoogle Scholar
  • 19 Khazen W, M'Bika JP, Collinet M et al. Differentiation-dependent expression of interferon gamma and toll-like receptor 9 in 3T3-F442A adipocytes. Biochimie 2007; 89: 669-675 DOI: 10.1016/j.biochi.2007.01.003.
    CrossrefPubMedGoogle Scholar
  • 20 Yamaguchi N, Argueta JG, Masuhiro Y et al. Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS letters 2005; 579: 6821-6826 DOI: 10.1016/j.febslet.2005.11.019.
    CrossrefPubMedGoogle Scholar
  • 21 Kopp A, Buechler C, Bala M et al. Toll-like receptor ligands cause proinflammatory and prodiabetic activation of adipocytes via phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase but not interferon regulatory factor-3. Endocrinology 2010; 151: 1097-1108 DOI: 10.1210/en.2009-1140.
    CrossrefPubMedGoogle Scholar
  • 22 Starr ME, Evers BM, Saito H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. The journals of gerontology Series A, Biological sciences and medical sciences 2009; 64: 723-730 DOI: 10.1093/gerona/glp046.
    PubMedGoogle Scholar
  • 23 Starr ME, Hu Y, Stromberg AJ et al. Gene expression profile of mouse white adipose tissue during inflammatory stress: age-dependent upregulation of major procoagulant factors. Aging cell 2013; 12: 194-206 DOI: 10.1111/acel.12040.
    CrossrefPubMedGoogle Scholar
  • 24 Green H, Kehinde O. An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell 1975; 5: 19-27
    CrossrefPubMedGoogle Scholar
  • 25 Zaitsu H, Serrero G. Pedersen fetuin contains three adipogenic factors with distinct biochemical characteristics. J Cell Physiol 1990; 144: 485-491
    CrossrefPubMedGoogle Scholar
  • 26 Bachmeier M, Loffler G. Adipogenic activities in commercial preparations of fetuin. Horm Metab Res 1994; 26: 92-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Green H, Kehinde O. Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol 1979; 101: 169-171
    CrossrefPubMedGoogle Scholar
  • 28 Green H, Meuth M. An established pre-adipose cell line and its differentiation in culture. Cell 1974; 3: 127-133
    CrossrefPubMedGoogle Scholar
  • 29 Cornelius P, MacDougald OA, Lane MD. Regulation of adipocyte development. Annu Rev Nutr 1994; 14: 99-129
    CrossrefPubMedGoogle Scholar
  • 30 MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 1995; 64: 345-373
    CrossrefPubMedGoogle Scholar
  • 31 Kopp A, Buechler C, Neumeier M et al. Innate immunity and adipocyte function: ligand-specific activation of multiple Toll-like receptors modulates cytokine, adipokine, and chemokine secretion in adipocytes. Obesity (Silver Spring) 2009; 17: 648-656
    CrossrefPubMedGoogle Scholar
  • 32 Moschen AR, Gerner RR, Tilg H. Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders. Current pharmaceutical design 2010; 16: 1913-1920
    CrossrefPubMedGoogle Scholar
  • 33 Waluga M, Hartleb M, Boryczka G et al. Serum adipokines in inflammatory bowel disease. World journal of gastroenterology: WJG 2014; 20: 6912-6917 DOI: 10.3748/wjg.v20.i22.6912.
    CrossrefPubMedGoogle Scholar
  • 34 Kopp A, Bala M, Buechler C et al. C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue. Endocrinology 2010; 151: 5267-5278 DOI: 10.1210/en.2010-0571.
    CrossrefPubMedGoogle Scholar
  • 35 Moschen AR, Kaser A. Enrich B et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 2007; 178: 1748-1758
    CrossrefPubMedGoogle Scholar
  • 36 Schmid A, Kopp A, Hanses F et al. C1q/TNF-related protein-3 (CTRP-3) attenuates lipopolysaccharide (LPS)-induced systemic inflammation and adipose tissue Erk-1/-2 phosphorylation in mice in vivo. Biochem Biophys Res Commun 2014; DOI: 10.1016/j.bbrc.2014.06.054.
    PubMedGoogle Scholar
  • 37 Schmid A, Kopp A, Hanses F et al. The novel adipokine C1q/TNF-related protein-3 is expressed in human adipocytes and regulated by metabolic and infection-related parameters. Experimental and clinical endocrinology & diabetes: official journal, German Society of Endocrinology [and] German Diabetes Association 2012; 120: 611-617 DOI: 10.1055/s-0032-1323803.
    PubMedGoogle Scholar
  • 38 Wang P, Mariman E, Keijer J et al. Profiling of the secreted proteins during 3T3-L1 adipocyte differentiation leads to the identification of novel adipokines. Cell Mol Life Sci 2004; 61: 2405-2417 DOI: 10.1007/s00018-004-4256-z.
    PubMedGoogle Scholar
  • 39 Nigro P, Pompilio G, Capogrossi MC. Cyclophilin A: a key player for human disease. Cell Death Dis 2013; 4: e888. DOI: 10.1038/cddis.2013.410
    PubMedGoogle Scholar