Exercise induces Mettl14 in iWAT but regulates browning and metabolism independently of Mettl14.

Exercise is a key driver of metabolic enhancement, and the impact of exercise on methyltransferase-like14 protein (Mettl14)-mediated N(6)-methyladenosine (m(6)A) modification remains unexplored. This study investigates the role of Mettl14 in inguinal white adipose tissue (iWAT) concerning exercise-induced metabolic improvement and its underlying mechanisms. We examined voluntary wheel-running exercise in C57BL/6N mice and Mettl14 heterozygous knockout (HET) mice models. We assessed metabolic phenotyping and molecular responses through body composition analysis, blood profiles, indirect calorimetry, real-time PCR, immunoblotting, and immunohistology. m(6)A levels were significantly elevated in the iWAT of trained mice, a result of increased Mettl14 expression. Additionally, higher Mettl14 levels induced by exercise were positively associated with browning markers in iWAT. Mettl14 HET led to increased weight gain and fat accumulation in a mechanism dependent on m(6)A levels. Furthermore, HET mice demonstrated notable reductions in oxygen consumption and energy expenditure at baseline. m(6)A levels were notably reduced in the iWAT of exercise-induced HET mice, yet the associated metabolic impairment was significantly mitigated. Exercise substantially correlates with enhanced browning and metabolic improvements by modulating m(6)A levels through Mettl14 expression in iWAT. However, this pathway does not critically regulate exercise-induced browning and the enhancement of whole-body metabolism. [BMB Reports 2025; 58(6): 269-275].