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PMID: 16691291 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.

The Journal of clinical investigation ·Vol. 116 ·No. 6 ·2006-06-00 ·Pages 1494-505

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M

Abstract

Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.

MeSH Terms
3T3 Cells Adipose Tissue/cytology,metabolism Animals Chemokine CCL2/blood,genetics Dietary Fats Fatty Liver Glucose/metabolism Humans Insulin Resistance Macrophages/metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Obese Mice, Transgenic Obesity/physiopathology Oligonucleotide Array Sequence Analysis RNA, Messenger/metabolism Triglycerides/metabolism
Chemicals
Ccl2 protein, mouse Chemokine CCL2 Dietary Fats RNA, Messenger Triglycerides Glucose
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kanda Hajime
Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Tateya Sanshiro
Tamori Yoshikazu
Kotani Ko
Hiasa Ken-ichi
Kitazawa Riko
Kitazawa Sohei
Miyachi Hitoshi
Maeda Sakan
Egashira Kensuke
Kasuga Masato
References (46)
46 references, click to expand
  1. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.
    Mol Cell. 1998 Aug;2(2):275-81 PMID: 9734366
  2. Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes.
    Biochem Biophys Res Commun. 2004 Apr 30;317(2):598-604 PMID: 15063799
  3. A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer.
    Mol Cell Biol. 1995 Sep;15(9):4851-5 PMID: 7651403
  4. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis.
    Nature. 1998 Aug 27;394(6696):894-7 PMID: 9732872
  5. Structure/activity analysis of human monocyte chemoattractant protein-1 (MCP-1) by mutagenesis. Identification of a mutated protein that inhibits MCP-1-mediated monocyte chemotaxis.
    J Biol Chem. 1994 Jun 3;269(22):15918-24 PMID: 8195247
  6. Evidence for a potent antiinflammatory effect of rosiglitazone.
    J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35 PMID: 15181049
  7. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT.
    J Clin Endocrinol Metab. 2005 Apr;90(4):2282-9 PMID: 15671098
  8. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
    Science. 1993 Jan 1;259(5091):87-91 PMID: 7678183
  9. Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants.
    J Exp Med. 1989 Apr 1;169(4):1449-59 PMID: 2926329
  10. Coomassie brilliant blue staining of lipids on thin-layer plates.
    Anal Biochem. 1984 Nov 1;142(2):406-10 PMID: 6084960
  11. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line.
    J Exp Med. 1989 Apr 1;169(4):1485-90 PMID: 2926331
  12. From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes.
    Diabetes. 2004 May;53(5):1285-92 PMID: 15111498
  13. CCR11 is a functional receptor for the monocyte chemoattractant protein family of chemokines.
    J Biol Chem. 2000 Mar 31;275(13):9550-6 PMID: 10734104
  14. SREBP-1 interacts with hepatocyte nuclear factor-4 alpha and interferes with PGC-1 recruitment to suppress hepatic gluconeogenic genes.
    J Biol Chem. 2004 Mar 26;279(13):12027-35 PMID: 14722127
  15. Obesity and the regulation of energy balance.
    Cell. 2001 Feb 23;104(4):531-43 PMID: 11239410
  16. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes.
    Diabetes. 2002 Jul;51(7):2045-55 PMID: 12086932
  17. Obesity and insulin resistance.
    J Clin Invest. 2000 Aug;106(4):473-81 PMID: 10953022
  18. Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4.
    J Clin Invest. 2001 Jul;108(1):153-60 PMID: 11435467
  19. Monocyte chemotactic protein-2 (MCP-2) uses CCR1 and CCR2B as its functional receptors.
    J Biol Chem. 1997 May 2;272(18):11682-5 PMID: 9115216
  20. Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice.
    J Biol Chem. 2003 Nov 21;278(47):46654-60 PMID: 13129912
  21. Troglitazone action is independent of adipose tissue.
    J Clin Invest. 1997 Dec 1;100(11):2900-8 PMID: 9389757
  22. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
    J Clin Invest. 2003 Dec;112(12):1821-30 PMID: 14679177
  23. Adipose tissue as an endocrine organ.
    Trends Endocrinol Metab. 2000 Oct;11(8):327-32 PMID: 10996528
  24. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver.
    Nature. 2001 Feb 8;409(6821):729-33 PMID: 11217863
  25. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.
    J Biol Chem. 1998 Oct 2;273(40):25573-80 PMID: 9748221
  26. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
    J Clin Invest. 1995 May;95(5):2409-15 PMID: 7738205
  27. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
    Nature. 2005 Jul 21;436(7049):356-62 PMID: 16034410
  28. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects.
    Int J Obes (Lond). 2005 Jan;29(1):146-50 PMID: 15520826
  29. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.
    Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5252-6 PMID: 2052604
  30. Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3.
    J Immunol. 1996 Dec 15;157(12):5613-26 PMID: 8955214
  31. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.
    Nat Med. 2001 Jun;7(6):699-705 PMID: 11385507
  32. Cloning and functional characterization of the rabbit C-C chemokine receptor 2.
    BMC Immunol. 2005 Jul 07;6:15 PMID: 16001983
  33. Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B.
    J Biol Chem. 1995 Dec 15;270(50):29671-5 PMID: 8530354
  34. Chemokines.
    Blood. 1997 Aug 1;90(3):909-28 PMID: 9242519
  35. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
    J Clin Endocrinol Metab. 1998 Mar;83(3):847-50 PMID: 9506738
  36. Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails.
    Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2752-6 PMID: 8146186
  37. Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels.
    J Lipid Res. 1999 May;40(5):967-72 PMID: 10224167
  38. Association between the A-2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus.
    Diabetologia. 2004 Sep;47(9):1574-80 PMID: 15349727
  39. A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo.
    Proc Natl Acad Sci U S A. 1990 Dec;87(24):9590-4 PMID: 2263614
  40. New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice.
    Circulation. 2001 Apr 24;103(16):2096-101 PMID: 11319201
  41. Importance of monocyte chemoattractant protein-1 pathway in neointimal hyperplasia after periarterial injury in mice and monkeys.
    Circ Res. 2002 Jun 14;90(11):1167-72 PMID: 12065319
  42. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.
    Endocr Rev. 2002 Apr;23(2):201-29 PMID: 11943743
  43. Obesity is associated with macrophage accumulation in adipose tissue.
    J Clin Invest. 2003 Dec;112(12):1796-808 PMID: 14679176
  44. CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
    J Clin Invest. 2006 Jan;116(1):115-24 PMID: 16341265
  45. Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1 monoclonal antibody.
    Hum Pathol. 1993 May;24(5):534-9 PMID: 7684023
  46. Monocyte chemoattractant protein 1 in obesity and insulin resistance.
    Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7265-70 PMID: 12756299
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI26498
Published
2006-06-00
Epub
2006-00-11
Pages
1494-505
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1459069
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI26498 PMC Full Text View journal details
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