WTAP Maintains Alternative Activation of Macrophages by Promoting IDH1-Mediated α-ketoglutarate Production

Background: N6-methyladenosine (m6A) modification plays a crucial role in various physiological processes by regulating mRNA biology. However, the exact impact of m6A modification on macrophages in adipose tissues under obese settings remains to be further elucidated. Methods: We established macrophage-specific Wtap-deficient mice to explore the effects of Wtap on obesity and metabolic disorders induced by high-fat diet (HFD) in mice. The molecular targets were explored by MeRIP-qPCR, and the metabolomic assays were performed to detect the alteration of relevant metabolites. Results: Wilms tumor 1-associated protein (WTAP), one of the m6A "writers", was downregulated in adipose tissue macrophages (ATMs) from obese individuals and negatively correlated with clinical metabolic traits. Depletion of Wtap in mouse macrophages exacerbated the metabolic consequences of high-fat diet (HFD) induced obesity. Additionally, energy expenditure and adipose beiging were considerably lower in Wtap-deficient mice in response to cold exposure. Mechanistic study revealed that WTAP-mediated m6A modification of isocitrate dehydrogenase 1 (Idh1) transcripts enhanced its stability and translation in macrophages leading to alpha-ketoglutarate (alpha-KG) production. Alpha-KG further supported alternative activation of macrophages by metabolic reprogramming. Conclusions: Our data support that Wtap modulates HFD-induced macrophages through interfering with the IDH1-alpha-KG axis, and highlight the importance of WTAP-mediated m6A modification in maintaining alternative macrophage activation, proposing potential targets for the regulation of obesity and related metabolic diseases.