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

<b>Background</b>: <i>N</i> ⁶-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. <b>Methods</b>: We established macrophage-specific <i>Wtap</i>-deficient mice to explore the effects of <i>Wtap</i> 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. <b>Results</b>: 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 <i>Wtap</i> in mouse macrophages exacerbated the metabolic consequences of high-fat diet (HFD) induced obesity. Additionally, energy expenditure and adipose beiging were considerably lower in <i>Wtap</i>-deficient mice in response to cold exposure. Mechanistic study revealed that WTAP-mediated m⁶A modification of isocitrate dehydrogenase 1 (<i>Idh1</i>) transcripts enhanced its stability and translation in macrophages leading to α-ketoglutarate (α-KG) production. Alpha-KG further supported alternative activation of macrophages by metabolic reprogramming. <b>Conclusions</b>: Our data support that <i>Wtap</i> modulates HFD-induced macrophages through interfering with the IDH1-α-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.