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 harbors a wide variety of immune cells that 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, with free fatty acids being used to build cell membranes and promote cell growth. “Enzymes such as ACC1, which regulate lipid metabolism, could favor the retention of ILC2 cells in lipid-rich environments such as adipose tissue,” says Prof. Christoph Wilhelm of 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 consumption drives metabolic dysfunction
The enzyme ACC1 is a key regulator of cellular metabolic balance. When fatty acids are scarce, it facilitates the production of long-chain fatty acids within the cells. If, on the other hand, sufficient fatty acids are present in the environment – for example, as a result of a high-fat diet (HFD) – the enzyme is inhibited to prevent further fat production. This is actually a useful mechanism – however, the inhibition impairs the maintenance and function of ILC2 immune cells. This leads to enlargement and inflammation of adipose tissue, predisposing mice to the development of diabetes. “We found that HFD-induced obesity in mice increases the uptake of fatty acids from the environment. This suppresses the enzyme ACC1 in the ILC2 cells of the adipose tissue,” says co-first author Fotios Karagiannis from Prof. Wilhelm’s research group. The researchers attribute this effect to the previously unrecognized role of ACC1 in maintaining the citrate shuttle across the inner mitochondrial membrane and an associated disruption of energy production in the mitochondria, which impairs the metabolic activity of ILC2 immune cells in the adipose tissue. “Taken together, our findings describe a self-reinforcing mechanism by which elevated levels of free fatty acids in obesity disrupt ILC2 metabolism and, consequently, the self-regulation of adipose tissue,” says co-first author Maria Rafailia Theodorou, formerly a doctoral student in Prof. Wilhelm’s research group.
Inhibition of ACC1 disrupts the activity of ILC2 immune cells
Through its research, the Bonn team discovered a link between the underlying causes of metaflammation to potential changes in the metabolism of immune cells. This is because certain side effects observed in the treatment of obesity and diabetes could be attributed to adverse effects on the metabolism of immune cells. “Thus, targeting of adipose tissue metabolism may fail without appropriate consideration of the effects on the immune system,” says Prof. Wilhelm, who is a member of the Cluster of Excellence ImmunoSensation3 as well as the Transdisciplinary Research Area (TRA) “Life and Health” at the University of Bonn. “A more comprehensive approach that considers immune cell metabolism could inform the development of more effective therapies in this area.”
Participating institutions and funding:
This study was conducted as part of the Collaborative Research Center (SFB) 1454 “Metaflammation and Cellular Programming” of the German Research Foundation (DFG) and the Cluster of Excellence ImmunoSensation3. SFB 1454 investigates the link between a Western lifestyle and chronic inflammatory diseases.
Publication: Fotios Karagiannis, Maria Rafailia Theodorou et al.: Adipose ILC2 cells depend on acetyl-CoA carboxylase 1 to maintain metabolic health; Cell Metabolism; DOI: https://doi.org/10.1016/j.cmet.2026.08.019
Scientific Contact:
Prof. Christoph Wilhelm
Institute of Clinical Chemistry and Clinical Pharmacology
University Hospital Bonn
Cluster of Excellence ImmunoSensation3 & TRA “Life and Health”, University of Bonn
Spokesperson and sub-project leader of Collaborative Research Centre (CRC) 1454
Email: cwilhelm@uni-bonn.de