Format

Send to

Choose Destination
Int J Obes (Lond). 2015 Nov;39(11):1607-18. doi: 10.1038/ijo.2015.104. Epub 2015 Jun 4.

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

Author information

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.

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.

PMID:
26041698
PMCID:
PMC5007876
DOI:
10.1038/ijo.2015.104
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center