MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2006 May 13

PMID 16691291

Citations 1178

Authors

Hajime Kanda

Sanshiro Tateya

Yoshikazu Tamori

Ko Kotani

Ken-Ichi Hiasa

Riko Kitazawa

Sohei Kitazawa

Hitoshi Miyachi

Sakan Maeda

Kensuke Egashira

Masato Kasuga

Affiliations

Soon will be listed here.

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.

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References

Gu L, Okada Y, Clinton S, Gerard C, Sukhova G, Libby P . Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2(2):275-81. DOI: 10.1016/s1097-2765(00)80139-2. View

Fasshauer M, Klein J, Kralisch S, Klier M, Lossner U, Bluher M . Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2004; 317(2):598-604. DOI: 10.1016/j.bbrc.2004.03.090. View

Zhang Y, Rollins B . A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer. Mol Cell Biol. 1995; 15(9):4851-5. PMC: 230730. DOI: 10.1128/MCB.15.9.4851. View

Boring L, Gosling J, Cleary M, Charo I . Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394(6696):894-7. DOI: 10.1038/29788. View

Zhang Y, RUTLEDGE B, Rollins B . 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; 269(22):15918-24. View

Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T . Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004; 89(6):2728-35. DOI: 10.1210/jc.2003-032103. View

Bruun J, Lihn A, Pedersen S, Richelsen B . 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; 90(4):2282-9. DOI: 10.1210/jc.2004-1696. View

Hotamisligil G, Shargill N, Spiegelman B . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259(5091):87-91. DOI: 10.1126/science.7678183. View

Yoshimura T, Robinson E, Tanaka S, Appella E, Kuratsu J, Leonard E . Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants. J Exp Med. 1989; 169(4):1449-59. PMC: 2189237. DOI: 10.1084/jem.169.4.1449. View

10.

Nakamura K, Handa S . Coomassie brilliant blue staining of lipids on thin-layer plates. Anal Biochem. 1984; 142(2):406-10. DOI: 10.1016/0003-2697(84)90484-6. View

11.

Matsushima K, Larsen C, DuBois G, Oppenheim J . Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med. 1989; 169(4):1485-90. PMC: 2189236. DOI: 10.1084/jem.169.4.1485. View

12.

Curat C, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R . From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004; 53(5):1285-92. DOI: 10.2337/diabetes.53.5.1285. View

13.

Schweickart V, Epp A, Raport C, Gray P . CCR11 is a functional receptor for the monocyte chemoattractant protein family of chemokines. J Biol Chem. 2000; 275(13):9550-6. DOI: 10.1074/jbc.275.13.9550. View

14.

Yamamoto T, Shimano H, Nakagawa Y, Ide T, Yahagi N, Matsuzaka T . SREBP-1 interacts with hepatocyte nuclear factor-4 alpha and interferes with PGC-1 recruitment to suppress hepatic gluconeogenic genes. J Biol Chem. 2004; 279(13):12027-35. DOI: 10.1074/jbc.M310333200. View

15.

Spiegelman B, Flier J . Obesity and the regulation of energy balance. Cell. 2001; 104(4):531-43. DOI: 10.1016/s0092-8674(01)00240-9. View

16.

Tamori Y, Masugi J, Nishino N, Kasuga M . Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002; 51(7):2045-55. DOI: 10.2337/diabetes.51.7.2045. View

17.

Kahn B, Flier J . Obesity and insulin resistance. J Clin Invest. 2000; 106(4):473-81. PMC: 380258. DOI: 10.1172/JCI10842. View

18.

Kim J, Zisman A, Fillmore J, Peroni O, Kotani K, Perret P . Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. J Clin Invest. 2001; 108(1):153-60. PMC: 353719. DOI: 10.1172/JCI10294. View

19.

Gong X, Gong W, Kuhns D, Ben-Baruch A, Howard O, Wang J . Monocyte chemotactic protein-2 (MCP-2) uses CCR1 and CCR2B as its functional receptors. J Biol Chem. 1997; 272(18):11682-5. DOI: 10.1074/jbc.272.18.11682. View

20.

Takahashi K, Mizuarai S, Araki H, Mashiko S, Ishihara A, Kanatani A . Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem. 2003; 278(47):46654-60. DOI: 10.1074/jbc.M309895200. View