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CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice

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Abstract

Aims/hypothesis

Obesity-induced inflammation is initiated by the recruitment of macrophages into adipose tissue. The recruited macrophages, called adipose tissue macrophages, secrete several proinflammatory cytokines that cause low-grade systemic inflammation and insulin resistance. The aim of this study was to find macrophage-recruiting factors that are thought to provide a crucial connection between obesity and insulin resistance.

Methods

We used chemotaxis assay, reverse phase HPLC and tandem MS analysis to find chemotactic factors from adipocytes. The expression of chemokines and macrophage markers was evaluated by quantitative RT-PCR, immunohistochemistry and FACS analysis.

Results

We report our finding that the chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1), identified from 3T3-L1 adipocyte conditioned medium, induces monocyte migration via its receptor chemokine (C-X-C motif) receptor 4 (CXCR4). Diet-induced obese mice demonstrated a robust increase of CXCL12 expression in white adipose tissue (WAT). Treatment of obese mice with a CXCR4 antagonist reduced macrophage accumulation and production of proinflammatory cytokines in WAT, and improved systemic insulin sensitivity.

Conclusions/interpretation

In this study we found that CXCL12 is an adipocyte-derived chemotactic factor that recruits macrophages, and that it is a required factor for the establishment of obesity-induced adipose tissue inflammation and systemic insulin resistance.

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Abbreviations

ATM:

Adipose tissue macrophages

CCL2:

Chemokine (C-C motif) ligand 2

CCR2:

Chemokine (C-C motif) receptor 2

CLS:

Crown-like structures

CM:

Conditioned medium

CXCL12:

Chemokine (C-X-C motif) ligand 12

CXCR4:

Chemokine (C-X-C motif) receptor 4

DIO:

Diet-induced obese

HFD:

High-fat diet

KO:

Knockout

MCP1:

Monocyte chemoattractant protein 1

MIF:

Macrophage migration factor

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCD:

Normal chow diet

RP:

Reverse phase

SCX:

Strong cation-exchange

SDF1:

Stromal cell-derived factor 1

SVC:

Stromal vascular cells

SVF:

Stromal vascular fraction

WAT:

White adipose tissue

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2013R1A2A1A03010110 and No.2010-0028684). This work was also funded by the GyeongSangBuk-Do Forestry Environment Research Institute.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

DK, JK, KY, POB, PGS and SHR contributed to the conception and design of the study. DK, JK, JHY, JG, PS, SoP, AL, CPH, MSJ, YK and SeP contributed to the acquisition of data. DK, JK, and CPH contributed to data analysis. DK, JK, JHY, JG, MHJ and SHR contributed to the interpretation of data. DK drafted the manuscript and JK, JHY, JG, KY, PS, SoP, AL, CPH, MSJ, YK, SeP, MHJ, POB, PGS and SHR revised it. All authors approved the final version to be published. SHR is the guarantor of this work.

Author information

Authors and Affiliations

  1. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, 790-784, Republic of Korea

    Dayea Kim, Jong Hyuk Yoon, Jaewang Ghim, Kyungmoo Yea, Parkyong Song, Soyeon Park, Areum Lee, Yonghoon Kwon, Sehoon Park & Sung Ho Ryu

  2. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden

    Jaeyoon Kim & Per-Olof Berggren

  3. Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Gyeongbuk, Republic of Korea

    Chun-Pyo Hong, Min Seong Jang & Myoung Ho Jang

  4. Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea

    Chun-Pyo Hong, Min Seong Jang, Myoung Ho Jang & Per-Olof Berggren

  5. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea

    Pann-Ghill Suh

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  1. Dayea Kim
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Corresponding author

Correspondence to Sung Ho Ryu.

Additional information

Dayea Kim and Jaeyoon Kim contributed equally to this study.

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Kim, D., Kim, J., Yoon, J.H. et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 57, 1456–1465 (2014). https://doi.org/10.1007/s00125-014-3237-5

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