期刊
GEROSCIENCE
卷 43, 期 3, 页码 1331-1347出版社
SPRINGER
DOI: 10.1007/s11357-021-00368-4
关键词
Adipose tissue; T lymphocyte; Macrophages; Glucose intolerance; Liver; Skeletal muscle
资金
- National Institutes of Health [K01 AG061271, R01 AG060395, R01 AG048366]
- Veteran's Affairs Merit Review Award from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service [I01 BX004492]
The study reveals that aging leads to increased T cell infiltration in eWAT, liver, and skeletal muscle, resulting in greater CD4+ and CD8+ cell numbers and a decreased CD4 to CD8 ratio. In old mice, T cells producing interferon-gamma and tumor necrosis factor-alpha accumulate in eWAT and liver, contributing to metabolic dysfunction associated with age. Anti-CD3 treatment improves glucose tolerance in old mice by enhancing insulin utilization and reducing gluconeogenesis-related gene expression in the liver.
Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab')2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-gamma and tumor necrosis factor-alpha are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-gamma. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.
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