| Author |
Khan, I. M. Perrard, X. Yd Brunner, G. Lui, H. Sparks, L. M. Smith, S. R. Wang, X. Shi, Z-Z Lewis, D. E. Wu, H. Ballantyne, C. M. |
| Description |
Country affiliation: United States Author Affiliation: Khan IM ( Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.); Perrard XY ( Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.); Brunner G ( Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.); Lui H ( Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.); Sparks LM ( Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.); Smith SR ( Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.); Wang X ( Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.); Shi ZZ ( Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA.); Lewis DE ( Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA.); Wu H ( Division of Infectious Diseases, Department of Internal Medicine, UT Health, Houston, TX, USA.); Ballantyne CM ( Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.) |
| 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. |
