Rationale: Clinical evidence suggests that the exposure to air pollution particulate matter (PM) is associated with the development of cardiometabolic disorders. Experimentally, we have shown that exposure to PM induces a local and systemic inflammatory response that involves various innate immune cells and soluble mediators, that leads to secondary visceral obesity and inflammation in adipose tissue. In the present study, we aim to further expand our understanding of the role of alveolar macrophages in promoting PM-induced inflammation, by defining cellular and humoral immune mediators of PM effects in the lung, and to further characterize the changes in adipose tissue biology and energy metabolism in PM-exposed mice.

Methods and Results: To evaluate the impact of PM on inflammation, metabolism, and obesity, male eight-week-old C57BL/6 mice were exposed to a PM surrogate (ROFA, Residual Oil Fly Ash) at 1 mg/kg body weight by intranasal instillation, or to urban air (UA) inside whole-body inhalation chambers located in a highly populated area of Buenos Aires City. Inflammatory cell recruitment was evident in the lungs of ROFA-exposed mice, with neutrophils peaking at 6 h post-exposure and macrophages peaking at 6 h and 72 h. We detected an increase of pro-inflammatory cytokine secretion that was evident in bronchoalveolar lavage fluid (BAL) immediately after PM-exposure and sustained in plasma over several days. Bulk RNA sequencing of sorted alveolar macrophages after PM-exposure revealed a proinflammatory gene signature after 6 hours encompassing (Cxcl10, Cxcl16 and Ccl3) and several pathways interfering with lipid metabolism. Increased protein levels of these mediators were confirmed in BAL and plasma samples from ROFA-exposed mice. In addition, we observed an increase in plasma norepinephrine levels. Despite ongoing adipose tissue inflammation and increased plasma catecholamines, we found decreased thermogenic gene expression in (Ucp-1, Elovl3, and Adrb3) suggesting blunted lipolysis and thermogenesis. This decrease in thermogenic capacity of brown adipose tissue was partially compensated by the increase in sarcolipin, a key mediator of non-shivering thermogenesis in muscle. Despite enhanced physical activity, ROFA-exposed mice showed significantly reduced heat production. Accordingly, mice breathing polluted air in a real-life exposure chamber over 16 weeks showed enhanced weight gain compared to control mice breathing filtered air that was caused by increased fat accumulation and adipocyte hypertrophy. Mechanistically, we found markers of increased white adipose tissue inflammation, altered lipid storage, an imbalance between lipid uptake and lipolysis, downregulation of thermogenesis, defective browning of visceral adipose tissue, altered levels of adipokines (leptin, adiponectin and GLP-1) and lack of sympathetic innervation in UA-exposed mice.

Conclusion: PM exposure alters overall energy metabolism and induces obesity by diminishing the metabolic capacity with brown adipose tissue, likely as a consequence of local and systemic inflammation. Our findings highlight the importance of considering environmental factors in cardiometabolic diseases.