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Integrative Biology

Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance

International Journal of Obesity volume 39, pages 1607–1618 (2015)Cite this article

Subjects

Abstract

Background/Objectives:

Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied.

Subjects/Methods:

T cells and macrophage markers were examined in SM of obese humans by reverse transcription-PCR (RT-PCR). Mice were fed high-fat diet (HFD) for 2–24 weeks, and time course of macrophage and T-cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-computed tomography (CT), and correlation to T-cell number in SM was examined. CD11a–/– mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T-cell accumulation in SM. To investigate the involvement of Janus kinase/signal transducer and activator of transcription (JAK/STAT), the major pathway for T helper I (TH1) cytokine interferon-γ, in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib.

Results:

Macrophage and T-cell markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T-cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T-cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T-cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice.

Conclusions:

Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM ‘adiposopathy' may thus have an important role in the development of insulin resistance and inflammation.

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Acknowledgements

This work was supported by NIH grants T32 GM88129 and T32 HL007812 (to IK), R01 HL098839 (to HW), P30 AI36211 (to DEL) and R01 DK078847 (to CMB). The authors thank Jerry L Perrard (Baylor College of Medicine) and Joshua Smith (Florida Hospital) for technical assistance, Ching H Tung, PhD (Houston Methodist Research Institute) for help with the CT imaging, Willa Hsueh, MD (Houston Methodist Research Institute) for donating mice for the micro-CT studies, Kerrie Jara (Baylor College of Medicine) for editorial assistance, Jacob Couturier (Department of Internal Medicine, UT Health, Houston, TX< USA) for help with the flow cytometry and the Mouse Metabolism Core at Baylor College of Medicine (under the Diabetes Research Center; supported by P30 DK079638) for help with insulin and glucose measurements. The authors also thank the human study participants.

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Authors and Affiliations

  1. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA

    I M Khan

  2. Division of Atherosclerosis and Vascular Medicine, Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA

    I M Khan, X-YD Perrard, G Brunner, H Lui, H Wu & C M Ballantyne

  3. Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA

    L M Sparks & S R Smith

  4. Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA

    X Wang & Z-Z Shi

  5. Division of Infectious Diseases, Department of Internal Medicine, UT Health, Houston, TX, USA

    D E Lewis

  6. Department of Pediatrics, Section of Leukocyte Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA

    H Wu & C M Ballantyne

  7. Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA

    C M Ballantyne

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  1. I M Khan
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Correspondence to C M Ballantyne.

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Khan, I., Perrard, XY., Brunner, G. et al. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes 39, 1607–1618 (2015). https://doi.org/10.1038/ijo.2015.104

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