title: CXCR3 modulates obesity-induced visceral adipose inflammation and systemic insulin resistance.
abstract: OBJECTIVE
  Chemokine (C-X-C motif) receptor 3 (CXCR3) is a chemokine receptor involved in the regulation of immune cell trafficking and activation. Increased CXCR3 expression in the visceral adipose of obese humans and mice was observed. A pathophysiologic role for CXCR3 in diet-induced obesity (DIO) was hypothesized.
  
  
  METHODS
  Wild-type (WT) C57B/L6J and chemokine receptor 3 knockout (CXCR3(-/-) ) mice were fed a high-fat diet (HFD) for 20 weeks followed by assessment of glucose metabolism and visceral adipose tissue (VAT) inflammation.
  
  
  RESULTS
  CXCR3(-/-) mice exhibited lower fasting glucose and improved glucose tolerance compared with WT-HFD mice, despite similar body mass. HFD-induced VAT innate and adaptive immune cell infiltration, including immature myeloid cells (CD11b(+) F4/80(lo) Ly6C(+) ), were markedly ameliorated in CXCR3(-/-) mice. In vitro IBIDI and in vivo migration assays demonstrated no CXCR3-mediated effect on macrophage or monocyte migration, respectively. CXCR3(-/-) macrophages, however, had a blunted response to interferon-γ, a TH 1 cytokine that induces macrophage activation.
  
  
  CONCLUSIONS
  A previously unreported role for CXCR3 in the development of HFD-induced insulin resistance (IR) and VAT macrophage infiltration in mice was demonstrated. Our results support pharmaceutical targeting of the CXCR3 receptor as a potential treatment for obesity/IR.
authors.affiliation: Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Deiuliis
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Duggineni
authors.forename: Jixin
authors.initials: J
authors.lastname: Zhong
authors.forename: Jessica
authors.initials: J
authors.lastname: Rutsky
authors.forename: Ambar
authors.initials: A
authors.lastname: Banerjee
authors.forename: Bradley
authors.initials: B
authors.lastname: Needleman
authors.forename: Dean
authors.initials: D
authors.lastname: Mikami
authors.forename: Vimal
authors.initials: V
authors.lastname: Narula
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hazey
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat; D018390:Gene Targeting; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007371:Interferon-gamma / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000503:physiopathology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; C515187:CXCR3 protein, human; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C515188:Cxcr3 protein, mouse; D007328:Insulin; D054367:Receptors, CXCR3; D014280:Triglycerides; D007371:Interferon-gamma