Children of obese mothers are more prone to metabolic disorders, even when they eat healthily, and a new study uncovers an early cellular shift in the developing liver that may explain why.
Study explains increased risk
of metabolic disorders in children born to obese mothers.
Children born to obese mothers face a
higher risk of developing metabolic disorders, even if they eat healthily
themselves. A new study from the University
of Bonn provides an explanation for this effect.
In obese mice, certain cells in the embryo’s liver are
reprogrammed during pregnancy, causing long-lasting changes to the offspring’s
metabolism. The researchers believe these findings may also apply to humans.
The study has been published in Nature.
The researchers focused on Kupffer cells, a type of
macrophage or “big eater” involved in the body’s innate immune system. During
embryonic development, these cells migrate to the liver, where they permanently
reside. In the liver, they help defend against pathogens and remove aging or
damaged cells.
“But these Kupffer cells also act as conductors,” explains Prof. Dr. Elvira Mass from the LIMES Institute at the University of Bonn. “They instruct the surrounding liver cells on what to do. In this way, they help ensure that the liver, as a central metabolic organ, performs its many tasks correctly.”
Permanently reprogram Kupffer cells.
This changes their function, causes liver cells (hepatocytes) to accumulate fat
and ultimately leads to a fatty liver. The graphic was created with
BioRender.com (http://BioRender.com). Credit: AG Mass/University of Bonn
Changing
the tune: From Beethoven to Vivaldi
Obesity appears
to alter the regulatory role of Kupffer cells. This conclusion comes from mouse
experiments conducted by Mass and collaborating research groups at the
University of Bonn. “We were able to show that the offspring of obese mothers
frequently developed a fatty liver shortly after birth,” says Dr. Hao Huang
from Mass’s lab. “And this happened even when the young animals were fed a completely
normal diet.”
The disorder seems to result from a type of “reprogramming” in the Kupffer cells of the offspring. These cells begin sending molecular signals that prompt liver cells to absorb more fat. Figuratively speaking, they stop conducting a Beethoven symphony and instead switch to a piece by Vivaldi.
More lipids (yellow, LD540) when exposed to molecules from Kupffer cells taken from the offspring of obese mice (right, HFDM). The image on the left shows liver cells exposed to factors from the offspring of mothers with normal weight (CDM). Cell nuclei are shown in cyan.
This shift already seems to occur
during embryonic development and is triggered by metabolic products from the
mother. These activate a kind of metabolic switch in the Kupffer cells and
change the way these cells direct 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 the molecular switch
When the
researchers genetically removed this switch in the Kupffer cells during
pregnancy, the offspring did not develop a fatty liver. Whether this mechanism
could also be targeted with medication is still unclear. The teams now plan to
investigate this in follow-up studies.
If new treatment approaches emerge from this, it would be good news. The altered behavior of the Kupffer cells likely has many negative consequences. Fat accumulation in the liver, for example, is accompanied by strong inflammatory responses. These can cause an increasing number of liver cells to die and be replaced with scar tissue. The result is fibrosis, which gradually impairs liver function. At the same time, the risk that liver cells degenerate and become cancerous increases.
“It is becoming ever more evident that many diseases
in humans already begin at a very early developmental stage,” says Mass, who is
also spokesperson 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 to explain in detail how this
early programming can happen.”
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 Fonds
and the European Molecular Biology Organization (EMBO).
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