title: Fractalkine is a novel human adipochemokine associated with type 2 diabetes.
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.
  
  
  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.
authors.affiliation: Division of Pediatric Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Rachana
authors.initials: R
authors.lastname: Shah
authors.forename: Christine C
authors.initials: CC
authors.lastname: Hinkle
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.forename: Nehal N
authors.initials: NN
authors.lastname: Mehta
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.forename: Mary E
authors.initials: ME
authors.lastname: Putt
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D047495:PPAR gamma; D019707:Receptors, Chemokine