Protein Found To Induce Tissue Stress

In a discovery that they say could lead to a better understanding of the causes of metabolic diseases—including obesity and diabetes—Harvard School of Public Health researchers recently found that overconsumption of lipids and other nutrients in mice activates a molecule that triggers the body’s inflammatory response.

Inflammation is the body’s necessary response to foreign pathogens, but chronic inflammation can cause serious tissue damage.

“The important question is, how can a metabolic signal or a nutrient trigger an immune response?” said Gökhan S. Hotamisligil, chair of the HSPH Department of Genetics and Complex Diseases and principal investigator for the study, which was published in the journal Cell on Feb. 5.

The researchers focused on the molecule known as PKR, an enzyme already known to be involved in the immune response against viruses.

After measuring the enzyme levels in the liver and fatty tissues from both lean and obese mice, they found that levels of PKR activation were strongly correlated with the amount of fatty tissue in the mice.

Their study—published in the February 5 issue of the journal Cell—postulates that activation of this enzyme leads to immune system subsequently interfering with metabolic pathways.

The study also shows that PKR directly interferes with normal insulin function in a way that could lead to the onset of type 2 diabetes.

“This discovery...can unify many previous studies related to inflammation and metabolic disease,” Hotamisligil said.

“It also identifies a mechanism of how nutrients can directly engage in such inflammatory response.”

PKR, after being activated by lipids and other nutrients, participates in the clustering of other molecules—creating a complex the researchers termed “metaflammasome”—which in turn leads to chronic inflammation.

The researchers are optimistic that their discovery of this additional function of PKR could lead to a better understanding of metabolic disorders and ultimately, to treatments.

Takahisa Nakamura, the first author of the study and a research fellow at HSPH, calls their work “the first step.”

“We’re very excited to analyze this new concept: that in cells, inflammatory pathways are integrated with metabolism,” Nakamura said.

The study may signal a new direction  in  metabolic disease research, according to James R. Mitchell, an assistant professor at HSPH who has researched the effects of dietary restriction on health in mammals.

“Understanding the specific mechanism of how lipids activate PKR could be the next exciting avenue of discovery,” Mitchell said.

—Staff writer Helen X. Yang can be reached at hxyang@fas.harvard.edu.