CD4⁺ T cells regulate glucose homeostasis independent of adipose tissue dysfunction in mice

Abstract

Obesity is frequently associated with a chronic low‐grade inflammation in the adipose tissue (AT) and impaired glucose homeostasis. Adipose tissue macrophages (ATMs) have been shown to accumulate in the inflamed AT either by means of recruitment from the blood or local proliferation. ATM proliferation and activation can be stimulated by TH2 cytokines, such as IL‐4 and IL‐13, suggesting involvement of CD4‐positive T cells in ATM proliferation and activation. Furthermore, several studies have associated T cells to alterations in glucose metabolism. Therefore, we sought to examine a direct impact of CD4‐positive T cells on ATM activation, ATM proliferation and glucose homeostasis using an in vivo depletion model. Surprisingly, CD4 depletion did not affect ATM activation, ATM proliferation, or insulin sensitivity. However, CD4 depletion led to a significant improvement of glucose tolerance. In line with this, we found moderate disturbances in pancreatic endocrine function following CD4 depletion. Hence, our data suggest that the effect on glucose metabolism observed after CD4 depletion might be mediated by organs other than AT and independent of AT inflammation.

The Role of IL-13 and IL-4 in Adipose Tissue Fibrosis

“…For immunofluorescence staining, AT explants were fixed in zinc formalin for 2 h and embedded in paraffin [ 64 ]. Paraffin sections were deparaffinized, unmasked in a pressure cooker at 120 °C in Tris/EDTA buffer (pH 9.5), and washed in PBS with 0.3% Triton.…”

IL-6 signaling drives self-renewal and alternative activation of adipose tissue macrophages

“…Of note, with our protocol we were not able to detect changes in Bromodesoxyuridine (BrdU) incorporation in AT leukocytes of obese Il6ra Dmyel and control animals (Supplementary Figures 2F, G). However, also different T-cell populations can affect ATM polarization and proliferation, which in turn affects insulin sensitivity and the outcome of diet-induced obesity (19)(20)(21). Therefore, we analyzed T-cell subsets isolated from obese AT of either Il6ra Dmyel or Il6ra fl/fl mice fed a NCD or HFD (Supplementary Figure 3).…”

What’s gut got to do with it? The role of the microbiota and inflammation in the development of adiposity and obesity

“…The number of T cell receptor αβ+ T cells in WAT correlates in a positive fashion with WAT mass [ 42 ] . T H cells guide the differentiation of WAT macrophage populations through cytokine production [ 43 , 44 ] . The direction of changes to specific T H subsets in WAT during obesity is less clear and seems to differ between models and experiments.…”

“…The direction of changes to specific T H subsets in WAT during obesity is less clear and seems to differ between models and experiments. For example, T H 1 cells tend to be positively associated with adiposity [ 44 , 45 ] , while T H 2 cells have been shown to increase [ 46 ] or decrease [ 43 ] , depending on the experimental conditions and timing of observations. Cytokines from T H 2 cells can polarize macrophages toward the more anti-inflammatory (alternatively activated) phenotype.…”