The reprogramming of Kupffer cells in embryos explains metabolic disorders in offspring

The reprogramming of Kupffer cells in embryos explains metabolic disorders in offspring

Children born to obese mothers are at higher risk of developing metabolic disorders, even if they follow a healthy diet themselves. A new study from the University of Bonn offers an explanation for this phenomenon. In obese mice, certain cells in the embryo's liver are reprogrammed during pregnancy. This leads to long-term changes in the metabolism of the offspring. The researchers believe these results could also be relevant to humans. The study has now been published in the journal Nature.

The team focused on the so-called Kupffer cells. These are macrophages-so-called “big eaters” that protect the body as part of the innate immune system. During embryonic development, they migrate to the liver, where they take up permanent residence. There they fight pathogens and break down aging or damaged cells.

These Kupffer cells also act as conductors. They instruct the surrounding liver cells about what to do. In this way, they help ensure that the liver, as a central metabolic organ, carries out its many tasks correctly. “

Prof. Dr. Elvira Messe from the Limes Institute at the University of Bonn

Changing the melody: from Beethoven to Vivaldi

However, it appears that this executive function is altered by obesity. This is what mouse experiments by mass have done in collaboration with other research groups at the University of Bonn. “We were able to show that the offspring of obese mothers often developed a fatty liver shortly after birth,” says Dr. Hao Huang from Mass's lab. “And this also happened when the young animals received a completely normal diet.”

The cause of this disorder appears to be a kind of “reprogramming” of the Kupffer cells in the offspring. As a result, they send out molecular signals that instruct liver cells to absorb more fat. In a figurative sense, they no longer perform Beethoven's symphonies, but Vivaldi's.

This shift appears to occur during embryonic development and is triggered by maternal metabolic products. These activate a type of metabolic switch in the Kupffer cells and change the way these cells guide liver cells in the long term. “This switch is a so-called transcription factor,” says Mass. “It controls which genes are active in Kupffer cells.”

No fatty liver without molecular switches

When the researchers genetically eliminated this change in the Kupffer cells during pregnancy, the offspring did not develop fatty liver disease. It is still unclear whether this mechanism could also be addressed with medication. The teams now plan to investigate this in follow-up studies.

If this leads to new treatment approaches, this would be good news. The altered behavior of the Kupffer cells is likely to have many negative consequences. For example, the accumulation of fat in the liver is accompanied by strong inflammatory reactions. These can cause an increasing number of liver cells to die and be replaced by scar tissue. The result is fibrosis, which gradually impairs liver function. At the same time, there is a risk of liver cells degenerating and becoming cancerous.

“It is becoming increasingly clear that many diseases in humans begin at a very early stage of development,” says Mass, who is also spokesman for the transdisciplinary research area “Life & Health” and a board member of the “Immunosensation2” Cluster of Excellence at the University of Bonn. “Our study is one of the few that can explain in detail how this early programming can happen.”

Participating institutes and funding:

In addition to the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE), the University of Vienna (Austria), Ghent University (Belgium) and Shanghai University (China) were involved in the study. The research was supported by the German Research Foundation (DFG, in particular SFB 1454 Metaflammation), the European Research Council (ERC), the Jürgen Manchot Foundation, the Boehringer Ingelheim Fund and the European Molecular Biology Organization (EMBO).

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