Fractalkine is a Novel Human Adipochemokine Associated with Type 2 Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2011 Apr 29

PMID 21525510

Citations 78

Authors

Rachana Shah

Christine C Hinkle

Jane F Ferguson

Nehal N Mehta

Mingyao Li

Liming Qu

Yun Lu

Mary E Putt

Rexford S Ahima

Muredach P Reilly

Affiliations

Soon will be listed here.

Abstract

Objective: Leukocyte infiltration of adipose is a critical determinant of obesity-related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown.

Research Design And Methods: CX3CL1 mRNA and protein were quantified in subcutaneous adipose and blood during experimental human endotoxemia and in lean and obese human adipose. CX3CL1 cellular source was probed in human adipocytes, monocytes, and macrophages, and CX3CL1-blocking antibodies were used to assess its role in monocyte-adipocyte adhesion. The association of genetic variation in CX3CR1 with metabolic traits was determined in a community-based sample. Finally, plasma CX3CL1 levels were measured in a case-control study of type 2 diabetes.

Results: Endotoxemia induced adipose CX3CL1 mRNA (32.7-fold, P < 1 × 10(-5)) and protein (43-fold, P = 0.006). Obese subjects had higher CX3CL1 levels in subcutaneous adipose compared with lean (0.420 ± 0.387 vs. 0.228 ± 0.187 ng/mL, P = 0.04). CX3CL1 was expressed and secreted by human adipocytes and stromal vascular cells. Inflammatory cytokine induction of CX3CL1 in human adipocytes (27.5-fold mRNA and threefold protein) was completely attenuated by pretreatment with a peroxisome proliferator-activated receptor-γ agonist. A putative functional nonsynonymous single nucleotide polymorphism (rs3732378) in CX3CR1 was associated with adipose and metabolic traits, and plasma CX3CL1 levels were increased in patients with type 2 diabetes vs. nondiabetics (0.506 ± 0.262 vs. 0.422 ± 0.210 ng/mL, P < 0.0001).

Conclusions: CX3CL1-CX3CR1 is a novel inflammatory adipose chemokine system that modulates monocyte adhesion to adipocytes and is associated with obesity, insulin resistance, and type 2 diabetes. These data provide support for CX3CL1 as a diagnostic and therapeutic target in cardiometabolic disease.

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References

Combadiere C, Potteaux S, Gao J, Esposito B, Casanova S, Lee E . Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003; 107(7):1009-16. DOI: 10.1161/01.cir.0000057548.68243.42. View

Anderson P, Mehta N, Wolfe M, Hinkle C, Pruscino L, Comiskey L . Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab. 2007; 92(6):2272-9. DOI: 10.1210/jc.2006-2545. View

McDermott D, Fong A, Yang Q, Sechler J, Cupples L, Merrell M . Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest. 2003; 111(8):1241-50. PMC: 152935. DOI: 10.1172/JCI16790. View

Umehara H, Bloom E, Okazaki T, Nagano Y, Yoshie O, Imai T . Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler Thromb Vasc Biol. 2003; 24(1):34-40. DOI: 10.1161/01.ATV.0000095360.62479.1F. View

Shi H, Kokoeva M, Inouye K, Tzameli I, Yin H, Flier J . TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006; 116(11):3015-25. PMC: 1616196. DOI: 10.1172/JCI28898. View

Agwunobi A, Reid C, Maycock P, Little R, Carlson G . Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab. 2000; 85(10):3770-8. DOI: 10.1210/jcem.85.10.6914. View

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

DHaese J, Demir I, Friess H, Ceyhan G . Fractalkine/CX3CR1: why a single chemokine-receptor duo bears a major and unique therapeutic potential. Expert Opin Ther Targets. 2010; 14(2):207-19. DOI: 10.1517/14728220903540265. View

Ferrante Jr A . Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med. 2007; 262(4):408-14. DOI: 10.1111/j.1365-2796.2007.01852.x. View

10.

Ghanim H, Abuaysheh S, Sia C, Korzeniewski K, Chaudhuri A, Fernandez-Real J . Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care. 2009; 32(12):2281-7. PMC: 2782991. DOI: 10.2337/dc09-0979. View

11.

Saederup N, Chan L, Lira S, Charo I . Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis. Circulation. 2008; 117(13):1642-8. PMC: 3589525. DOI: 10.1161/CIRCULATIONAHA.107.743872. View

12.

Lee S, Namkoong S, Kim Y, Kim C, Lee H, Ha K . Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways. Am J Physiol Heart Circ Physiol. 2006; 291(6):H2836-46. DOI: 10.1152/ajpheart.00113.2006. View

13.

Kasama T, Wakabayashi K, Sato M, Takahashi R, Isozaki T . Relevance of the CX3CL1/fractalkine-CX3CR1 pathway in vasculitis and vasculopathy. Transl Res. 2009; 155(1):20-6. DOI: 10.1016/j.trsl.2009.08.009. View

14.

Cook D, Chen S, Sullivan L, Manfra D, Wiekowski M, Prosser D . Generation and analysis of mice lacking the chemokine fractalkine. Mol Cell Biol. 2001; 21(9):3159-65. PMC: 86945. DOI: 10.1128/MCB.21.9.3159-3165.2001. View

15.

Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M . Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell. 1997; 91(4):521-30. DOI: 10.1016/s0092-8674(00)80438-9. View

16.

Bagheri R, Qasim A, Mehta N, Terembula K, Kapoor S, Braunstein S . Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. Am J Cardiol. 2010; 106(8):1118-23. PMC: 3108486. DOI: 10.1016/j.amjcard.2010.06.028. View

17.

Jung S, Aliberti J, Graemmel P, Sunshine M, Kreutzberg G, Sher A . Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000; 20(11):4106-14. PMC: 85780. DOI: 10.1128/MCB.20.11.4106-4114.2000. View

18.

Sirois-Gagnon D, Chamberland A, Perron S, Brisson D, Gaudet D, Laprise C . Association of common polymorphisms in the fractalkine receptor (CX3CR1) with obesity. Obesity (Silver Spring). 2010; 19(1):222-7. DOI: 10.1038/oby.2010.125. View

19.

Coenen K, Gruen M, Lee-Young R, Puglisi M, Wasserman D, Hasty A . Impact of macrophage toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice. Diabetologia. 2008; 52(2):318-28. PMC: 2615827. DOI: 10.1007/s00125-008-1221-7. View

20.

Mehta N, McGillicuddy F, Anderson P, Hinkle C, Shah R, Pruscino L . Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2009; 59(1):172-81. PMC: 2797919. DOI: 10.2337/db09-0367. View