A group of innate immune cells known as group 2 innate lymphoid cells (ILC2s) are essential for maintaining a healthy metabolic balance in adipose tissue. Obesity significantly impairs the number and function of ILC2s, contributing to the progression of metabolic inflammation. How ILC2s are disrupted by obesity has so far remained unclear. Researchers from Bonn University Hospital (UKB) and the University of Bonn have now shown in obese mice that acetyl-CoA carboxylase 1 (ACC1), a key enzyme in fatty acid biosynthesis, is a crucial regulator of the maintenance and function of ILC2 immune cells in adipose tissue. The findings provide an explanation for the adverse effects of inhibiting acetyl-CoA carboxylase in obesity. The results have now been published in the journal Cell Metabolism.
Recent lifestyle changes, such as reduced physical activity and increased consumption of energy-dense, processed foods, have dramatically increased the prevalence of obesity and diabetes worldwide. Although the development of obesity-related metabolic diseases is complex, it is primarily driven by persistent, low-grade inflammation known as metaflammation. Adipose tissue contains a wide variety of immune cells that help maintain the balance between energy supply, blood glucose levels and lipid metabolism by promoting an anti-inflammatory environment. This balance is disrupted in obesity, leading to fundamental changes in adipose tissue.
ILC2 immune cells are involved in lipid metabolism, using free fatty acids to build cell membranes and support cell growth. “Enzymes such as ACC1, which regulate lipid metabolism, could help ILC2s remain in lipid-rich environments such as adipose tissue,” says Prof. Christoph Wilhelm from the Institute of Clinical Chemistry and Clinical Pharmacology at the UKB. “We found that these immune cells are metabolically impaired in obesity.”
Increased fatty acid uptake drives metabolic dysfunction
The enzyme ACC1 is an important regulator of cellular metabolism. When only small amounts of fatty acids are available, it is used to produce long-chain fatty acids within cells. When sufficient fatty acids are available in the surrounding environment, for example as a result of a high-fat diet (HFD), the enzyme is inhibited to prevent further fat production. While this is normally a useful mechanism, switching off ACC1 impairs the maintenance and function of ILC2 immune cells. This leads to enlargement and inflammation of adipose tissue, making mice more susceptible to developing diabetes.
“We found that HFD-induced obesity in mice increases the uptake of fatty acids from the surrounding environment. As a result, the enzyme ACC1 is suppressed in ILC2 cells in adipose tissue,” says co-first author Fotios Karagiannis from Prof. Wilhelm’s research group. The researchers attribute this effect to a previously unrecognised role of ACC1 in maintaining the citrate shuttle across the inner mitochondrial membrane and the associated disruption of energy production in mitochondria. This process supports the metabolic activity of ILC2 immune cells in adipose tissue.
“Taken together, our findings show how increased levels of free fatty acids in obesity trigger a self-reinforcing mechanism that disrupts ILC2 metabolism and, consequently, the self-regulation of adipose tissue,” says co-first author Maria Rafailia Theodorou, who was previously a PhD student in Prof. Wilhelm’s research group.
Inhibiting ACC1 disrupts ILC2 immune cell activity
The Bonn team’s research links the underlying causes of metaflammation to potential changes in immune cell metabolism. Certain side effects observed during the treatment of obesity and diabetes could potentially be related to adverse effects on immune cell metabolism.
“Therefore, specifically targeting metabolism in adipose tissue without adequately considering the effects on the immune system could fail,” says Prof. Wilhelm, who is a member of the ImmunoSensation³ Cluster of Excellence and the Transdisciplinary Research Area (TRA) “Life and Health” at the University of Bonn. “A more comprehensive approach that takes immune cell metabolism into account could contribute to the development of more effective therapies.”
Institutions and funding
This study was conducted as part of Collaborative Research Centre (CRC) 1454 “Metaflammation and Cellular Programming”, funded by the German Research Foundation (DFG), and the ImmunoSensation³ Cluster of Excellence. CRC 1454 investigates the relationship between a Western lifestyle and chronic inflammatory diseases.
Publication:
Fotios Karagiannis, Maria Rafailia Theodorou et al.: Adipose ILC2 depend on acetyl-CoA carboxylase 1 to maintain metabolic health; Cell Metabolism; DOI: 10.1016/j.cmet.2026.08.019
Scientific contact
Prof. Christoph Wilhelm
Institute of Clinical Chemistry and Clinical Pharmacology
Bonn University Hospital
ImmunoSensation³ Cluster of Excellence & TRA “Life and Health”, University of Bonn
Spokesperson and Principal Investigator of CRC 1454
Email: cwilhelm@uni-bonn.de
Media contact
Dr. Inka Väth
Deputy Press Spokesperson, Bonn University Hospital (UKB)
Communications and Media Office, Bonn University Hospital
Phone: (+49) 228 287-10596
Email: inka.vaeth@ukbonn.de
