Inflammation, adipose tissue and T cells: What is the “straight skinny” on lean versus fat mice?

To the Editor

Obesity is associated with chronic inflammation in adipose tissue (AT), evidenced by increased levels of cytokines/chemokines and accumulation and activation of macrophages and T cells,^1-3 which are acknowledged as important contributors to insulin resistance in obesity. Recently, using apoe^−/−xCD4dnTGFbR mice, Sultan et al reported that T cell–mediated inflammation does not cause insulin resistance in lean mice.⁴ Compared to controls (apoe^−/− mice), lean apoe^−/−xCD4dnTGFbR mice showed increased inflammation in AT (but not specifically in AT), indicated by increased content of T cells and macrophages, higher levels of TNF-α, IFN-γ, and MCP-1, but a comparable level of IL-6.⁴ However, lean apoe^−/−xCD4dnTGFbR mice did not show worsened insulin resistance compared to apoe^−/− mice.⁴ Therefore, the authors concluded that T cell–mediated inflammation in AT does not cause insulin resistance in hyperlipidemic mice.⁴

We acknowledge Sultan et al for the first report on the study of the role of T cell–mediated inflammation in insulin resistance.⁴ However, because of the following limitations of this study, we feel that it is too early to make any firm conclusions on the potential role of T cell–mediated AT inflammation in metabolic dysfunctions, particularly with diet-induced obesity, which is commonly accompanied by dyslipidemia.

First, apoe^−/−xCD4dnTGFbR mice displayed a unique inflammation pattern in AT, with unchanged IL-6 level compared to apoe^−/− controls, but lower IL-6 level than B6 mice.⁴ However, obese mice show increased IL-6 level compared to leans. Thus, this mouse model does not represent the AT inflammation pattern observed in obesity, and therefore may have little if any relevance to the T cell–mediated AT inflammation in obesity. The pathophysiology of the lipid disorders associated with insulin resistance and obesity, particularly as related to fatty acid metabolism, is markedly different than the apoe^−/− model.

Second, the authors used lean mice.⁴ When we and others study the role of chronic AT inflammation in insulin resistance, we mostly refer to obese conditions and examine the contribution of obesity-related inflammation to metabolic dysfunctions. Results obtained in lean mice in a study of the role of inflammation per se in insulin resistance may have little direct relevance to obese conditions.

Third, this study used female mice.⁴ Most previous studies of obesity-related inflammation used male mice.^{1, 5, 6} As we showed previously,² female mice were less predisposed to develop insulin resistance than male mice with obesity, even though they were maintained on the same type of high-fat diet for the same period of time. Therefore, it is unclear whether a gender effect existed in this study.⁴

Fourth, in addition to T cells, macrophages were also increased and activated in AT of apoe^−/−xCD4dnTGFbR. The absence of impaired insulin sensitivity in apoe^−/−xCD4dnTGFbR mice was also in conflict with a role of macrophage-mediated AT inflammation in insulin resistance as previously demonstrated by several research labs.^{5, 6}

Fifth, the authors provided some evidence indicating that the lack of IL-6 upregulation may contribute to the absence of insulin resistance in apoe^−/−xCD4dnTGFbR mice.⁴ They also suggested that upregulation of 11β-HSD1 in AT of apoe^−/−xCD4dnTGFbR (compared to apoe^−/−) mice contributed to the lack of IL-6 upregulation in this mouse model. However, they did not show a significant difference between apoe^−/−xCD4dnTGFbR and apoe^−/− in AT IL-6 levels. Both apoe^−/−xCD4dnTGFbR and apoe^−/− mice had lower IL-6 levels in AT than B6. The authors might assume that the increased 11β-HSD1, which catalyzes generation of cortisol, in AT of apoe^−/−xCD4dnTGFbR may have counterbalanced the effect of the increased cytokines (TNF-α, MCP-1, etc.) on IL-6 regulation in apoe^−/−xCD4dnTGFbR because these cytokines were low in AT of apoe^−/− mice. However, the low levels of cytokines (including IL-6) in AT of apoe^−/− mice as compared to B6 were accompanied by insulin resistance, as the authors observed in apoe^−/− mice,⁴ which does not support a key role of IL-6 in insulin resistance.⁴

In summary, Sultan et al reported some novel phenotypic changes of lean apoe^−/−xCD4dnTGFbR mice in AT and metabolic functions, which are caused by loss of TGF-β–dependent inhibition of T-cell activation.⁴ However, because of the limitations of this study, the potential contribution of T cell–mediated AT inflammation to insulin resistance with diet-induced obesity, which is the major mechanism driving this problem in humans, clearly requires additional study.