How the immune system influences metabolism during fasting

Diet and lifestyle 14. apr 2022 2 min Postdoctoral Fellow Anne Loft, Assistant Professor Søren Fisker Schmidt Written by Kristian Sjøgren

Researchers have identified several signals that the immune system transmits to hepatocytes, the metabolic cells of the liver, during fasting. These signals affect the ability of hepatocytes to produce ketone bodies, an important source of energy during fasting that further provide many health benefits. When the researchers removed a key regulatory factor controlling the transmission of the inflammatory signals in fasting mice, the production of ketone bodies in their hepatocytes decreased.

Fasting benefits health. One way is by reducing inflammation, which is involved in developing obesity and type 2 diabetes. Now new surprising research shows that macrophages, which are the immune cells that initiate inflammation, actually benefit fasting and the processes in the liver during fasting.

The results indicate that the immune system transmits lower levels of certain pro-inflammatory signalling molecules to the hepatocytes during fasting, causing them to increase their production of ketone bodies, an important and healthy source of energy.

The study thus provides new insight into how fasting and the immune system interact in a healthy and fit body.

“Many people think that the immune system is only active when combatting illness, but the immune system is also active when we are healthy. This study demonstrated that the cells of the immune system change the signals that are transmitted to hepatocytes during fasting, thereby affecting the production of ketone bodies,” explains a researcher behind the study, Anne Loft, Postdoctoral Fellow, Center for Functional Genomics and Tissue Plasticity (ATLAS), Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.

The research has been published in Cell Metabolism.

Identified active genes during fasting

Fasting has many beneficial effects on inflammatory processes.

Conversely, inflammation can also affect metabolic processes, and the researchers wanted to determine how the immune system affects metabolism when healthy subjects fast – something researchers do not yet know much about.

The researchers examined the macrophages in mouse livers as well as the hepatocytes, which are the key metabolic cells in the liver capable of converting sugar and fat into energy.

The mice fasted for up to 24 hours, and then the researchers examined the gene expression in the hepatocytes and macrophages to see which genes are active during fasting.

By comparing the active genes with databases of protein function, the researchers found several proteins that could be signalling molecules that the macrophages direct towards the hepatocytes during fasting.

“We used bioinformatics to investigate how the various cells can influence each other during fasting and which signalling molecules the macrophages use to control the hepatocytes,” says another main author, Søren Fisker Schmidt, Assistant Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.

Fasting induces the macrophages to send healthy signals

In the next part of the research, the researchers created a genetically engineered mouse that had a gene-regulating factor removed in the macrophages. This factor is normally activated during fasting and inhibits the production of the inflammatory signalling molecules.

The study showed that these engineered mice sent higher levels of certain pro-inflammatory signals to the hepatocytes during fasting than normal mice, which lead to reduced production of ketone bodies in the hepatocytes.

Anne Loft says that this indicates that the gene-regulating factor is essential for the macrophages to signal to the hepatocytes to produce ketone bodies during fasting.

“Overall, the study indicates that fasting enables the inflammatory cells to play a fine-tuning role for the ability of hepatocytes to produce an alternative energy source in the form of ketone bodies, which other studies further have shown have long-term beneficial health effects. Conversely, eating excessively for a long time can lead to a chronic inflammatory condition, inhibiting some of these metabolic reactions in the body, showing how the interaction between the immune system and metabolism depend strongly on the nutritional context ,” explains Anne Loft.

No magic pill

Anne Loft and Søren Fisker Schmidt think that the discovery mainly contributes to basic research and knowledge about how the immune system, metabolism and fasting interact to keep the body healthy and well.

It might be tempting to think that this discovery could lead to potential drugs with similar effects on the hepatocytes as the macrophages during fasting.

The idea is interesting, but the researchers warn that the various signalling pathways cannot just be stimulated artificially because they affect many more cell systems and in more places in the body than the liver.

“This study helps our understanding of basic mechanisms of the immune system among healthy people and how they influence metabolism,” says Søren Fisker Schmidt.

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis” has been published in Cell Metabolism. Most of the study was carried out in the laboratory of Professor Stephan Herzig at the Helmholtz Diabetes Center in Munich, where Anne Loft and Søren Fisker Schmidt were affiliated as postdoctoral researchers funded by the Novo Nordisk Foundation.

In the Functional Genomics & Metabolism Research Unit, we use advanced genomic tools to understand the transcriptional plasticity and regulatory netwo...

Søren Fisker Schmidt is an Assistant Professor at the Department of Biochemistry and Molecular Biology, University of Southern Denmark since 2021. He...

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