T‐Cell Recruitment and Th1 Polarization in Adipose Tissue During Diet‐Induced Obesity in C57BL/6 Mice

Abstract

The role of adaptive immunity in obesity-associated adipose tissue (AT) inflammation and insulin resistance (IR) is controversial. We employed flow cytometry and quantitative PCR to assess T-cell recruitment and activation in epididymal AT (eAT) of C57BL/6 mice during 4-22 weeks of a high (60% energy) fat diet (HFD). By week 6, eAT mass and stromal vascular cell (SVC) number increased 3-fold in mice fed HFD, coincident with onset of IR. We observed no increase in the proportion of CD3+ SVCs or in gene expression of CD3, IFNγ, or regulated upon activation, normal T-cell expressed and secreted (RANTES) during the first 16 weeks of HFD. In contrast, CD11c+ macrophages (Mφ) were enriched 6-fold by week 8 (p < 0.01). SVC enrichment for T cells (predominantly CD4+ and CD8+) and elevated IFNγ and RANTES gene expression were detected by 20-22 weeks of HFD (p < 0.01), coincident with the resolution of eAT remodeling. HFD-induced T cell priming earlier in the obesity time course is suggested by (1) elevated (5-fold) IL-12p40 gene expression in eAT by week 12 (p ≤ 0.01) and (2) greater IFNγ secretion from PMA/ionophorestimulated eAT explants at week 6 (1 fold, p = 0.08) and week 12 (5 fold, p < 0.001). In summary, T cell enrichment and IFNγ gene induction occur subsequent to ATMφ recruitment, onset of IR and resolution of eAT remodeling. However, enhanced priming for IFNγ production suggests the contribution of CD4+ and/or CD8+ effectors to cell-mediated immune responses promoting HFDinduced AT inflammation and IR.

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…In adipose tissue there was a marked increase in inflammatory markers after 16 weeks of HFD, but this was not associated with activation of the inflammatory kinases JNK and IKK. Consistent with our data, other studies have shown that macrophage infiltration and inflammation are only present in adipose tissue following prolonged (≥8 week) fat feeding [41][42][43]. A recent study by Lee et al [7] did report the early presence of some inflammatory markers in adipose tissue of fat-fed mice; however, their studies showed that inflammation is not an early driver of insulin resistance, but may play a role in the maintenance of longer-term obesityinduced insulin resistance.…”

“…A recent study by Lee et al [7] did report the early presence of some inflammatory markers in adipose tissue of fat-fed mice; however, their studies showed that inflammation is not an early driver of insulin resistance, but may play a role in the maintenance of longer-term obesityinduced insulin resistance. Collectively, the data from the current study and the literature [41][42][43][44] demonstrate there is a dissociation between the initiation of insulin resistance and the development of macrophage-associated inflammation. However, because of the wide variety of cells and markers associated with systemic inflammation it is possible that other immune cells show activation at this early stage [45].…”

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

“…Investigation of the inflammatory state of adipose tissue in the different strains of HFD-fed mice indicated substantial evidence of macrophage infiltration (increased F4/80 and Cd11c gene expression) in all strains and evidence of increased cytokine expression (Tnfa and mcp1) in three of the five strains including BALB/c. These results demonstrate that adipose tissue inflammation can be observed within 8 weeks of starting an HFD, even in the presence of normal glucose tolerance and insulin action in BALB/c mice, and thus support the notion that inflammation may only contribute to glucose intolerance and insulin resistance after long-term high-fat feeding [42,43]. It should be noted that this study examined specific biomarkers that have often been suggested as important factors influencing the development of metabolic disease.…”

Adipogenesis

“…It is now largely accepted that TNFa expression in adipose tissue comes from macrophages (Weisberg et al 2003). More recent studies have shown that IFNg is produced from both NK cells (O'Rourke et al 2009) and T cells (Rocha et al 2008;Duffaut et al 2009;Strissel et al 2010;Yang et al 2010) present in adipose tissue. Together, these studies suggest that immune cells in adipose tissue produce TNFa and IFNg, which can inhibit differentiation of preadipocytes and induce insulin resistance in mature adipocytes.…”