Ilvira M Khan1, Xiao-Yuan Dai Perrard2, Jerry L Perrard2, Amir Mansoori2, C Wayne Smith3, Huaizhu Wu4, Christie M Ballantyne5. 1. Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; 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. Section of Leukocyte Biology, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. 4. 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. 5. 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. Electronic address: cmb@bcm.tmc.edu.
Abstract
OBJECTIVES: High-fat diet (HFD) feeding in mice is characterized by accumulation of αβ T cells in adipose tissue. However, the contribution of αβ T cells to obesity-induced inflammation of skeletal muscle, a major organ of glucose uptake, is unknown. This study was undertaken to evaluate the effect of αβ T cells on insulin sensitivity and inflammatory state of skeletal muscle and adipose tissue in obesity. Furthermore, we investigated whether CD4+IFNγ+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity. METHODS: Mice lacking αβ T cells (T cell receptor beta chain-deficient [TCRb-/-] mice) were fed HFD for 12 weeks. Obesity-induced skeletal muscle and adipose tissue inflammation was assessed by flow cytometry and quantitative RT-PCR. To investigate the effect of TH1 cells on skeletal muscle and adipose tissue inflammation and metabolic functions, we injected 5×10(5) TH1 cells or PBS weekly over 12 weeks into HFD-fed TCRb-/- mice. We also cultured C2C12 myofibers and 3T3-L1 adipocytes with TH1-conditioned medium. RESULTS: We showed that similar to adipose tissue, skeletal muscle of obese mice have higher αβ T cell content, including TH1 cells. TCRb-/- mice were protected against obesity-induced hyperglycemia and insulin resistance. We also demonstrated suppressed macrophage infiltration and reduced inflammatory cytokine expression in skeletal muscle and adipose tissue of TCRb-/- mice on HFD compared to wild-type obese controls. Adoptive transfer of TH1 cells into HFD-fed TCRb-/- mice resulted in increased skeletal muscle and adipose tissue inflammation and impaired glucose metabolism. TH1 cells directly impaired functions of C2C12 myotubes and 3T3-L1 adipocytes in vitro. CONCLUSIONS: We conclude that reduced adipose tissue and skeletal muscle inflammation in obese TCRb-/- mice is partially attributable to the absence of TH1 cells. Our results suggest an important role of TH1 cells in regulating inflammation and insulin resistance in obesity.
OBJECTIVES: High-fat diet (HFD) feeding in mice is characterized by accumulation of αβ T cells in adipose tissue. However, the contribution of αβ T cells to obesity-induced inflammation of skeletal muscle, a major organ of glucose uptake, is unknown. This study was undertaken to evaluate the effect of αβ T cells on insulin sensitivity and inflammatory state of skeletal muscle and adipose tissue in obesity. Furthermore, we investigated whether CD4+IFNγ+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity. METHODS:Mice lacking αβ T cells (T cell receptor beta chain-deficient [TCRb-/-] mice) were fed HFD for 12 weeks. Obesity-induced skeletal muscle and adipose tissue inflammation was assessed by flow cytometry and quantitative RT-PCR. To investigate the effect of TH1 cells on skeletal muscle and adipose tissue inflammation and metabolic functions, we injected 5×10(5) TH1 cells or PBS weekly over 12 weeks into HFD-fed TCRb-/-mice. We also cultured C2C12 myofibers and 3T3-L1 adipocytes with TH1-conditioned medium. RESULTS: We showed that similar to adipose tissue, skeletal muscle of obesemice have higher αβ T cell content, including TH1 cells. TCRb-/-mice were protected against obesity-induced hyperglycemia and insulin resistance. We also demonstrated suppressed macrophage infiltration and reduced inflammatory cytokine expression in skeletal muscle and adipose tissue of TCRb-/-mice on HFD compared to wild-type obese controls. Adoptive transfer of TH1 cells into HFD-fed TCRb-/-mice resulted in increased skeletal muscle and adipose tissue inflammation and impaired glucose metabolism. TH1 cells directly impaired functions of C2C12 myotubes and 3T3-L1 adipocytes in vitro. CONCLUSIONS: We conclude that reduced adipose tissue and skeletal muscle inflammation in obeseTCRb-/-mice is partially attributable to the absence of TH1 cells. Our results suggest an important role of TH1 cells in regulating inflammation and insulin resistance in obesity.
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