Long-term exposure to fine air pollution can impair metabolic health by disrupting the normal function of brown fat in mice. A study co-led by the University of Zurich shows that this occurs through complex changes in gene regulation driven by epigenetic mechanisms. The results demonstrate how environmental pollutants contribute to the development of insulin resistance and metabolic diseases.

There is growing evidence that air pollution is not just harmful to our lungs and heart, but also plays a significant role in the development of metabolic disorders like insulin resistance and type 2 diabetes. A new study co-led by Francesco Paneni, professor at the Center for Translational and Experimental Cardiology of the University of Zurich (UZH) and the University Hospital Zurich (USZ), and Sanjay Rajagopalan, professor at the Case Western Reserve University, Cleveland, now sheds light on the topic.

Mice exposed to concentrated tiny particles in the air
The researchers aimed to better understand how long-term exposure to fine air pollutants might affect the body’s ability to regulate blood sugar and maintain metabolic health. They focused on a specific type of pollution known as PM_2.5, which refers to tiny airborne particles smaller than 2.5 micrometers that can be inhaled deeply into the lungs. For their investigation, the researchers exposed laboratory mice to either filtered air or concentrated PM_2.5 for six hours a day, five days a week, over a period of 24 weeks. This setup was designed to closely mimic chronic urban exposure in humans.

Particular attention was paid to brown adipose tissue, a special type of fat that helps the body generate heat and burn calories, and therefore plays a key role in energy balance and glucose metabolism. After the exposure period of about five months, the mice that had inhaled PM_2.5 showed signs of disrupted metabolism, including impaired insulin sensitivity. Further examination revealed that the function of brown fat had been significantly altered. “In particular, we found that the expression of important genes in brown adipose tissue which regulate its ability to produce heat, process lipids and handle oxidative stress were disturbed. These changes were accompanied by increased fat accumulation and signs of tissue damage and fibrosis within the tissue,” says Paneni.

Two enzymes are main drivers for epigenetic changes
The researchers then examined the underlying mechanisms driving these changes. They found that air pollution had triggered significant changes in the regulation of DNA in brown fat cells. This included modifications in DNA methylation patterns and changes in how accessible certain genes were for being turned on or off – a process known as chromatin remodeling. These epigenetic changes affect how cells function by regulating gene activity without altering the genetic code itself.

Two enzymes were identified as main drivers of this process: HDAC9 and KDM2B. These enzymes are involved in modifying histones, the proteins around which DNA is wrapped. They were found to bind to specific regions of the DNA in brown fat cells of the mice exposed to PM_2.5, leading to a reduction in key chemical tags, or methyl groups, that normally promote gene activity. “When these enzymes were experimentally suppressed, brown fat function improved, whereas increasing their activity led to further declines in metabolism,” Paneni adds.

New targets for prevention or treatment
The study shows that long-term exposure to fine air pollution can impair metabolic health by disrupting the normal function of brown fat. This occurs through complex changes in gene regulation controlled by epigenetic mechanisms. “Our findings help explain how environmental pollutants like PM_2.5 contribute to the development of insulin resistance and metabolic disease, and they point to potential new targets for prevention or treatment,” says Francesco Paneni.