Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5

Abstract

Background Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFα), lymphotoxin α (LTα), and lymphotoxin β (LTβ) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. Methods and results LTα/TNFα/LTβ triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. Conclusion The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.

Metabolomics analysis of a mouse model for chronic exposure to ambient PM2.5

“…These clusterings strongly suggest that chronic CAP exposure markedly altered the circulating metabolome. They are consistent with numerous previous studies showing that chronic ambient PM 2.5 exposure correlates with various systemic and/or extra-pulmonary effects (Chen et al, 2017;Chen et al, 2018;Gorr et al, 2014;Hu et al, 2017;Sancini et al, 2014;Zhang et al, 2017). Notably, in spite of those numerous studies investigating the toxicity of chronic ambient PM 2.5 exposure, its biomarker(s) has not yet been established.…”

Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice

“…We had three mice in each group with heterogeneous results. Of note, an increase in the expression of any of the aforementioned genes impaired energy metabolism, as demonstrated 20,28,29 .…”

“…Previously studies have shown that the inhibition of tumor necrosis factor-alpha (TNF-α) or the use of the IKKβ inhibitor in the hypothalamus of mice chronically exposed to PM 2.5 reduce inflammation in peripheral tissues 16,17,29 . The above studies suggest a link between hypothalamic inflammation induced by PM 2.5 exposure and metabolic dysfunction.…”

Exposure to concentrated ambient PM2.5 alters the composition of gut microbiota in a murine model

“…Chronic exposure to CAP has been shown to result in glucose intolerance and insulin resistance in various mouse models [ 29 , 30 ]. Figure 1b and c reveal that consistent with these previous studies, the 12-month exposure to CAP versus FA significantly impaired mouse glucose tolerance and induced a marked insulin resistance.…”