environmental nanoparticles and adipocyte-macrophage crosstalk

Final Scientific Report: Executive summary BSF2011178 – Assaf Rudich; James J. Schauer: Potential role of atmospheric nano-particle pollutants in the pathogenesis of obesity through modulation of adipocyte-macrophage crosstalk This proposal addressed an emerging notion derived from epidemiological and some mechanistic studies, that environmental pollutants may contribute to the pathogenesis of obesity, or more specifically – to its adverse metabolic impact. We hypothesized that macrophages may be “first-line cell responders” to environmental particles (PM), and mediate an adverse functional impact on adipocytes (fat cells).

During the funding period, we have teamed to collaboratively challenge this hypothesis using both in-vitro (cellular) systems and in-vivo models (lean or obese mice exposed to extracts of particulate matter which we have collected, and chemically characterized). Within 3 published joint papers, an additional manuscript in final preparation, and an MSc thesis, our main findings are: (i.) Single lung exposure to PM extracts induces a local and transient inflammatory and oxidative stress response, without “spillover” of the response systemically. (2) This confinement of the response can potentially be attributed to the induction of defense mechanisms, such as antioxidant and detoxification mechanisms. (3) The metal content in the PM extract is largely responsible for the inflammatory, oxidative, but also to the defense mechanism induction. (4) The inflammatory and oxidative effects of repeated exposure “spills over” from the lung to the systemic level. (5) This may be attributed to “exgaustion” of the repair/protective/defense mechanisms. (6) As, Fe and Zn may constitute the main metals responsible for lung macrophages activation. (7) PM-activated macrophages can induce insulin resistance of adipocytes. (8) An interaction exists between obesogenic diet and exposure to PM extracts, activating a tissue-specific response, which may be at least partially mediated by epigenetic alterations (DNA methylation).

The impact of this research may be significant: It highlights the need to consider monitoring and perhaps regulating/limiting environmental particles’ content of metals, specifically As, Fe, and Zn. Also, it may be suggested that in order to prevent systemic effects of environmental exposure to pollutants, future studies should explore ways of enhancing the antioxidative defense, possibly related to the Nrf2 systems. Finally, macrophages may be a crucial mediator in the link between environmental exposure, obesity, and metabolic (and adipose tissue) dysfunction.