CXCR3 modulates obesity-induced visceral adipose inflammation and systemic insulin resistance

Authors


  • Funding agencies: This research was supported by an NRSA grant (F32-DK083903) and a KL2 fellowship (Award Number Grant 8KL2TR000112-05 from the National Center for Advancing Translational Sciences) to Dr. Deiuliis. This work was additionally supported by RO-1-ES017290 and R21-DK088522 grants to Dr. Rajagopalan

  • Disclosure: The authors declare no conflict of interest.

  • Author contributions: JAD conceived and carried out the experiment including study design (SD), data collection (DC), data analysis (DA), data interpretation (DI), generation of figures (GF), and manuscript composition (MC). S.O. —DC; D.D. —DC, DA; J.Z. —SD, DI; J.R. —DC, manuscript editing (ME); A.B. —DC; B.N. —DC; D.M. —DC; V.M. —DC; J.H. —DC; A.R.S.—SD, DA, DI, ME; S.R. —SD, MC, ME.

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+ F4/80lo 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 TH1 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.

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