A type of defense cell that is present throughout the body, but in low quantities, could be a key to understanding how obesity and liver damage caused by excess medications or the accumulation of fat in the organ develop.
In a study published in the journal Cell Reports, a group led by researchers from the State University of Campinas (Unicamp) showed that a type of T lymphocyte, known by the acronym iNKT, contributes to regulating obesity and is involved in liver damage.
“This cell is found in several organs, but in adipose tissue it appears to have a regulatory function, which helps control obesity. While in the spleen and liver it is involved in controlling inflammation. Now, we can better understand how this occurs”, explains Cristhiane Favero Aguiar, first author of the study and FAPESP postdoctoral fellow at the Institute of Biology (IB) at Unicamp.
“iNKTs occur at a very low frequency, less than 1% of our circulating leukocytes are of this type. However, they respond quickly and intensely to pathogens or molecules that demand a response and therefore have an important anti-inflammatory role in some contexts, such as adipose tissue”, says Pedro Moraes-Vieira, professor at IB-Unicamp supported by FAPESP and study coordinator.
The researcher explains that, until then, it was known that, as one becomes obese, the number of these cells decreases. However, how this happened was still a mystery. The group then used the transcriptome technique, which shows everything that is expressed in a given tissue or cell. With this, he found different genes in the iNKT of adipose tissue, spleen and liver that could play an important role in their function.
Same cell, different functions
In experiments with mice, the researchers observed that the iNKT found in the liver and spleen are similar from a metabolic point of view, depending on glucose to be activated. By deactivating the Pkm2 gene, linked to glucose production, in the iNKT found in these organs, their ability to mitigate acute liver injury was impaired.
On the other hand, the same cells found in adipose tissue depend on another gene, AMPK, to fulfill their function in that tissue. When the gene was deactivated, preventing the production of a protein linked to lipid metabolism, the cells lost the ability to maintain their own functioning in balance. As a result, they could no longer regulate the inflammation caused by obesity in adipose tissue.
In other analyses, the researchers measured the content of mitochondria – organelles that produce energy for the cell – and observed that it was similar in the liver and spleen. However, in adipose tissue iNKT, mitochondria had a smaller mass and a more spherical shape.
Other measurements showed even more reactive oxygen species in the iNKT of adipose tissue, which could be a sign of an imbalance in the system. Furthermore, they detected a greater presence of fatty acid metabolism proteins, linked to obesity.
These results suggest that the microenvironment around the cells influences the immunometabolic profile of iNKT, which may have direct consequences for their functionality.
The researchers then injected obese mice with healthy iNKT taken from adipose tissue, which caused the animals to lose weight. The effect was not observed when iNKT that did not produce AMPK was injected.
“We were able to deepen our knowledge about the specific immunometabolic regulation of each of these tissues by iNKT cells. This directly impacts the course of inflammation caused by liver damage and obesity”, concludes Aguiar, currently a postdoctoral fellow at Trinity College in Dublin, Ireland.
The study had the collaboration of professor Alexandre Keller, from the Federal University of São Paulo (Unifesp), and groups from the University of São Paulo (USP). It was also supported by FAPESP through eight other projects (13/07607-8, 15/15626-8, 19/25973-8, 19/19435-3, 19/06372-3, 19/11490-5, 21/ 11200-7 and 18/21018-9).
Access the article: Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury
