ABSTRACT
Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health.
Subject(s)
Adipose Tissue , Inflammation , Mitochondria , Particulate Matter , Vehicle Emissions , Animals , Vehicle Emissions/toxicity , Mitochondria/metabolism , Mitochondria/drug effects , Mice , Particulate Matter/adverse effects , Particulate Matter/toxicity , Adipose Tissue/metabolism , Adipose Tissue/drug effects , Inflammation/metabolism , Inflammation/chemically induced , Inflammation/pathology , Male , Mice, Inbred C57BL , Energy Metabolism/drug effects , Adipokines/metabolism , Air Pollutants/adverse effects , Air Pollutants/toxicity , Adipocytes/metabolism , Adipocytes/drug effectsABSTRACT
Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors of the immunoglobin superfamily prominently expressed by lung epithelium. Previous experiments demonstrated that over-expression of RAGE by murine alveolar epithelium throughout embryonic development causes neonatal lethality coincident with significant lung hypoplasia. In the current study, we evaluated the expression of NKX2.1 (also referred to as TTF-1), a homeodomain-containing transcription factor critical for branching morphogenesis, in mice that differentially expressed RAGE. We also contextualized NKX2.1 expression with the abundance of FoxA2, a winged double helix DNA binding protein that influences respiratory epithelial cell differentiation and surfactant protein expression. Conditional RAGE over-expression was induced in mouse lung throughout gestation (embryonic day E0-18.5), as well as during the critical saccular period of development (E15.5-18.5), and analyses were conducted at E18.5. Histology revealed markedly less lung parenchyma beginning in the canalicular stage of lung development and continuing throughout the saccular period. We discovered consistently decreased expression of both NKX2.1 and FoxA2 in lungs from transgenic (TG) mice compared to littermate controls. We also observed diminished surfactant protein C in TG mice, suggesting possible hindered differentiation and/or proliferation of alveolar epithelial cells under the genetic control of these two critical transcription factors. These results demonstrate that RAGE must be specifically regulated during lung formation. Perturbation of epithelial cell differentiation culminating in respiratory distress and perinatal lethality may coincide with elevated RAGE expression in the lung parenchyma.