Airborne PM 2.5-Induced Hepatic Insulin Resistance by Nrf2/JNK-Mediated Signaling Pathway

Int J Environ Res Public Health. 2017 Jul 14;14(7):787. doi: 10.3390/ijerph14070787.

Abstract

Animal and epidemiological studies have suggested that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is associated with the risk of developing type 2 diabetes. However, the mechanism underlying this risk is poorly understood. In the present study, we investigated the effects of PM2.5 exposure on glucose homeostasis and related signaling pathways in mice. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2-/-) C57BL/6 male mice were exposed to either ambient concentrated PM2.5 or filtered air (FA) for 12 weeks through a whole-body PM exposure system. At the end of the exposure, we assessed liver damage, and performed metabolic studies, gene expressions, as well as molecular signal transductions to determine the signaling pathways involving oxidative responses, insulin signaling, and glucose metabolism. Our results indicated that PM2.5 exposure for 12 weeks caused significant liver damage as evidenced by elevated levels of aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, PM2.5 exposure induced impaired glucose tolerance and inhibited glycogen synthesis, leading to hepatic insulin resistance indicated by higher glucose levels, higher area under the curve (AUC), and homeostasis model assessment of insulin resistance (HOMA-IR) values. We further found that PM2.5 exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes. Moreover, PM2.5 exposure activated the c-Jun N-terminal kinase (JNK) signaling pathway and increased insulin receptor substrate-1 (IRS-1) phosphorylation at Ser307, but reduced protein kinase B phosphorylation at Ser473. Taken together, our study demonstrated PM2.5 exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic insulin resistance.

Keywords: JNK/IRS-1/AKT; Nrf2; PM2.5; insulin resistance; liver; oxidative stress.

MeSH terms

  • Air Pollutants / toxicity*
  • Animals
  • Insulin Resistance*
  • Liver / drug effects*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2* / genetics
  • Particle Size
  • Particulate Matter / toxicity*
  • Signal Transduction / drug effects

Substances

  • Air Pollutants
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Particulate Matter