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

  • Int J Obes (Lond). 2015 Nov;39(11):1607-18. doi: 10.1038/ijo.2015.104.
I M Khan  1  2 ,  X Yd Perrard  2 ,  G Brunner  2 ,  H Lui  2 ,  L M Sparks  3 ,  S R Smith  3 ,  X Wang  4 ,  Z-Z Shi  4 ,  D E Lewis  5 ,  H Wu  2  6 ,  C M Ballantyne  2  6  7
Affiliations
  • 1. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 2. Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 3. Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
  • 4. Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA.
  • 5. Division of Infectious Diseases, Department of Internal Medicine, UT Health, Houston, TX, USA.
  • 6. Section of Leukocyte Biology, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 7. Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
PMID: 26041698 DOI: 10.1038/ijo.2015.104
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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