Children of overweight mothers often develop overweight and metabolic diseases such as fatty liver – even if they eat healthy. A new study now shows a mechanism in mice that could also occur in humans and explain this phenomenon. Accordingly, metabolic products from obese mothers intervene in the liver development of the embryo during pregnancy. Certain immune cells in the liver are reprogrammed so that the child’s fat metabolism changes in the long term, as the team reports in “Nature”.
Overweight leads to an obesity of the liver in the long run. This is accompanied by massive inflammation, which means that life -threatening diseases such as fibrosis or tumors can develop over time. Earlier studies had shown that the so-called Kupapfer cells are involved when adults develop liver diseases such as fatty liver due to an unhealthy lifestyle. These cells “live” in the liver and belong to the macrophages, the food cells of the immune system. They dispose of pathogens and old liver and blood cells.
“The Kupffer cells also take on the role of a conductor,” explains Elvira Mass from the University of Bonn. “They instruct the liver cells around them what they have to do. They ensure that this central metabolism organ can correctly perform its diverse tasks.” For example, these cells help with blood formation or with fat metabolism. It is also known that the Kupffer cells hike out of the yolk sac into the liver of the embryo during pregnancy, then stay there and adapt to their liver-specific tasks. So far, however, it was unclear how the lifestyle and metabolism of the mother affects the development of the embryonic liver functions.
Fat liver by reprogramming during pregnancy
Researchers around Mass and their colleagues Hao Huang have now examined this using mice. “We were able to show that the descendants of overweight mother animals often developed a fatty liver shortly after birth,” explains Huang. “Even when the young animals died as normal.” In order to find out why this is and what happens on molecular and genetic level in the liver of the embryos, the researchers carried out a number of experiments.
The team stated that the Kupfer cells of the young animals poured out special signal molecules, so-called apolipoproteins, whereupon the surrounding liver cells increasingly recorded lipid and developed a fatty liver. Huang and his colleagues concluded from the fact that the mutuality of the mother changed the conductor function of the Kupffer cells and reprogrammed them. But how exactly does that happen?
As further tests showed, the mother’s metabolism intervenes the metabolism of the embryo during pregnancy. Certain lipids and fatty acids of the mother get into the liver of the offspring via the blood. There you activate a central switch of the embryonic copper cells-the transcription factor (HIF1α)-and thus permanently convert genetic activity in the liver. “This transcription factor controls which genes are read in the Kupffer cells,” says Mass. Among other things, it ensures the release of apolipoproteins, which then lead to fat storage.
Maternal influence also in humans
In follow-up studies, the researchers now want to investigate whether this switch can be deactivated in the Kupffer cells by medication so that the liver of the young animals works normally and no fatty liver forms later. If such active ingredients can be found, new treatment options for affected people may also result. Because Huang and his colleagues assume that the same reprogramming of the gene activity in embryonic copper cells of mice also happens during pregnancy from overweight women-which is why their children often often develop overweight as well as metabolic disorders and diseases of the liver.
Source: Hao Huang (University of Bonn) et al.; Nature, DOI: 10.1038/S41586-025-09190-W
