title: Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.|Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Khan
authors.affiliation: Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: X Yd
authors.initials: XY
authors.lastname: Perrard
authors.affiliation: Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Brunner
authors.affiliation: Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lui
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Sparks
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Z-Z
authors.initials: ZZ
authors.lastname: Shi
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, UT Health, Houston, TX, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Lewis
authors.affiliation: Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Section of Leukocyte Biology, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Section of Leukocyte Biology, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Ballantyne
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology*; D009765:Obesity / Q000473:pathology*; D016176:T-Lymphocyte Subsets; D055114:X-Ray Microtomography