In this study, we investigated the effects of inhalation exposure to PM2.5 on oxidative stress, inflammatory response, mitochondria and adipocyte-specific gene expression in adipose tissue depots. To our knowledge, this is the first study to systematically evaluate the effect of ambient PM2.5 on WAT and BAT specific genes in different adipose depots. There are several major findings in this study. First, exposure to PM2.5 resulted in oxidative stress in BAT. Second, exposure to PM2.5 induced changes consistent with reduced BAT functionality and a regression to a WAT phenotype [decrease in BAT specific genes (Pgc-1α, Dio2, Ucp1) and increase in WAT-specific genes (Hoxc9 and Igfbp3)]. This shift was not seen in WAT, when the same genes were analyzed. Finally, mitochondrial number was reduced in both eWAT and iBAT in response to PM2.5 exposure.
Recent studies have implicated PM2.5 in increased adipose inflammation and insulin resistance [11, 12], and epidemiological studies indicate that obesity is associated with adverse health risks, such as hypertension and atherosclerosis . PM2.5 has been shown to stimulate generation of reactive oxygen species (ROS) in cells due to its small diameters and large surface area . To test if PM2.5 exposure could trigger ROS production in vivo, we examined the redox states in BAT. O2
- production was significantly increased in BAT in PM2.5-exposed mice compared with FA-exposed mice.
PM exposure has been demonstrated to cause mitochondrial damage in the pulmonary and cardiovascular systems [32, 33], but little is known about the effects of PM2.5 on mitochondria in adipose tissues. In our study, we showed, by TEM measurement, that mitochondrial number was significantly decreased in response to PM2.5 exposure in both eWAT and iBAT, while the mitochondrial area was reduced in the eWAT depots as well. The possible mechanisms may include increased adipocyte membrane permeability or induced apoptosis caused by ROS .
BAT functional alterations in response to various stimuli have been investigated for many years but adaptation in BAT as a pathophysiological entity has only been recently investigated. Alterations in BAT function may influence propensity to obesity . Indeed, prior studies suggest alteration of brown adipose gene expression in response to obesity and diabetes [36, 37]. In addition to modulation of BAT functionality, there has been considerable interest in "brown-like adipose cells" in WAT. These so called "brite" cells are present in WAT as evidenced by the presence of UCP1 expressing cells in WAT. Studies in cell culture indicate that brown adipocytes and muscle cells share a common origin, which is distinct from white adipocytes . A series of experiments has demonstrated that the UCP1 expressing cells constitute a subset of adipocytes ("brite" adipocytes) with a developmental origin and molecular characteristics . The functional significance of these cells is not known, however; the presence of such cells in WAT raises important questions regarding potential regulatory pathways that may enhance or decrease "brown-fat" like functionality to WAT. In conditions of chronic cold exposure white-to-brown conversion meets the need of thermogenesis, while an obesogenic diet induces brown-to-white conversion, to meet the need of storing excess energy .
In this study, we found evidence of important changes in BAT in response to PM2.5 exposure. BAT expends energy through sympathetic nervous system-mediated non-shivering thermogenesis, where UCP1 is the key player [41, 42]. UCP1 was significantly decreased in the iBAT. In addition, morphometric evaluation of TEM images indicated that mitochondrial number and size in BAT and the number (but not size) in WAT were reduced in response to PM2.5 exposure. Taken together, these data suggest that PM2.5 exposure may compromise the functionality of iBAT.
We found that PM2.5 exposure induces down-regulation of Ucp1, Pgc-1α, Dio2 and Elovl3 genes (change in Elovl3 seen only in mBAT) in classic BAT depots. On the other hand, WAT-specific genes Hoxc9 and Igfbp3 were up-regulated in brown adipose tissue, indicating brown adipocytes may potentially transform to a white adipose phenotype when stimulated by PM2.5 exposure. Interestingly, a similar shift was not seen in WAT suggesting that this phenotype is relatively specific for BAT.
Why these changes occur in BAT are beyond the scope of this paper, primarily due to limitations of sample size and tissue availability in each group. However, it is interesting to postulate that the increased vascularity of BAT may potentially relate to its vulnerability to air-pollution mediated effects. Future studies would need to be designed to provide significant insights into the roles and mechanisms of PM2.5-associated physiology and pathology.
In summary, our data demonstrate the important effects of PM2.5 exposure on oxidative stress and mitochondrial alterations in adipose tissues. These findings may have a significant impact on our understanding of the adverse effects of particulate air pollution on cardio-metabolic diseases, especially in the context of obesity and insulin resistance.