Over the last decades the prevalence of obesity and type 2 diabetes developed into a major threat to public health. Group 2 innate lymphoid cells (ILC2) residing in the adipose tissue play an important role in maintaining the metabolic health and energy balance of the organisms. However, in obesity ILC2 are lost leading to the progression of metabolic inflammation. We found that high-fat diet (HFD) results in a metabolic reprogramming of adipose ILC2 impairing mitochondrial function and expression of the enzyme Acetyl-CoA carboxylase 1 (ACC1). Deletion of ACC1 in ILC2 leads to an overall reduction of ILC2 impairing their function, which ultimately leads to increased adipose tissue weight. We further find that HFD-feeding or deletion of ACC1 results in the accumulation of undifferentiated ILC2 and ILC progenitors in the adipose tissue. Thus, obesity could predominately impair ILC2 differentiation and activation by impacting on the expression of ACC1. Based on these findings, we aim to understand how ACC1 controls ILC2 metabolism and differentiation. As ACC1 depends on cytoplasmic citrate, we hypothesise that obesity impairs ILC2 differentiation and activation by affecting the citrate shuttle, thus blocking alternative TCA cycling. We aim to identify the main cellular fuels used in the TCA cycle and test whether ILC2 employ a non-canonical TCA cycle by cycling of cytoplasmic and mitochondrial citrate and malate. To test this hypothesis as a general concept beyond type 2 immunity we aim to understand the interplay of ACC1, the citrate shuttle and canonical and non-canonical TCA cycling in the metabolic control and differentiation of type 2 and type 1 immunity driving metaflammation.

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