Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM_2.5

Exposure to ambient fine particulate matter (PM_2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM_2.5 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 PM_2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined.

LTα/TNFα/LTβ triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM_2.5 (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.

The present study suggests that TNF/LT deficiency influences PM_2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.