Summary 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. In obesity ILC2 numbers are reduced and their function is impaired, leading to the progression of metabolic inflammation. However, which events impact on ILC2 biology in the adipose tissue in obesity remains unresolved. Here, we find that high fat diet (HFD)-induced obesity in mice results in the metabolic reprogramming of adipose ILC2, impairing mitochondrial function and the expression of the enzyme Acetyl-CoA carboxylase 1 (ACC1). Investigating a possible connection between ACC1 and obesity-induced changes in ILC2, we show that fatty acids directly reduce the expression of ACC1, while pharmacological inhibition of ACC1 diminishes mitochondrial function and ILC2 metabolism. Furthermore, deletion of ACC1 in ILC2 phenocopies the overall reduction and functional impairment of ILC2 observed in obesity, which ultimately leads to increased triglycerides in circulation, adipose tissue hypertrophy and inflammation, even in the absence of HFD. Through single-cell RNA sequencing analysis we uncover that HFD-feeding or deletion of ACC1 results in the accumulation of undifferentiated ILC2 and ILC progenitors in the adipose tissue, suggesting that ACC1 may primarily regulate the maturation of ILC2. Together, these results reveal that obesity could predominately impair adipose ILC2 differentiation and activation by impacting on the expression of ACC1, rather than inducing cell death through lipid overload and lipotoxicity.

Anabolic lipid metabolism regulates adipose type 2 innate lymphoid cell differentiation to maintain metabolic health