Exercise induces Mettl14 in iWAT but regulates browning and metabolism independently of Mettl14
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Exercise is a key driver of metabolic enhancement, and the impactof exercise on methyltransferase-like14 protein (Mettl14)-mediatedN6-methyladenosine (m6A) modification remains unexplored. This study investigates the role of Mettl14 in inguinalwhite adipose tissue (iWAT) concerning exercise-inducedmetabolic improvement and its underlying mechanisms. Weexamined voluntary wheel-running exercise in C57BL/6N miceand Mettl14 heterozygous knockout (HET) mice models. Weassessed metabolic phenotyping and molecular responsesthrough body composition analysis, blood profiles, indirectcalorimetry, real-time PCR, immunoblotting, and immunohistology. m6A levels were significantly elevated in the iWAT oftrained mice, a result of increased Mettl14 expression. Additionally,higher Mettl14 levels induced by exercise werepositively associated with browning markers in iWAT. Mettl14HET led to increased weight gain and fat accumulation in amechanism dependent on m6A levels. Furthermore, HET micedemonstrated notable reductions in oxygen consumption andenergy expenditure at baseline. m6A levels were notably reducedin the iWAT of exercise-induced HET mice, yet the associatedmetabolic impairment was significantly mitigated. Exercisesubstantially correlates with enhanced browning and metabolicimprovements by modulating m6A levels through Mettl14expression in iWAT. However, this pathway does not criticallyregulate exercise-induced browning and the enhancement ofwhole-body metabolism.
Abstract
Exercise is a key driver of metabolic enhancement, and the impactof exercise on methyltransferase-like14 protein (Mettl14)-mediatedN6-methyladenosine (m6A) modification remains unexplored. This study investigates the role of Mettl14 in inguinalwhite adipose tissue (iWAT) concerning exercise-inducedmetabolic improvement and its underlying mechanisms. Weexamined voluntary wheel-running exercise in C57BL/6N miceand Mettl14 heterozygous knockout (HET) mice models. Weassessed metabolic phenotyping and molecular responsesthrough body composition analysis, blood profiles, indirectcalorimetry, real-time PCR, immunoblotting, and immunohistology. m6A levels were significantly elevated in the iWAT oftrained mice, a result of increased Mettl14 expression. Additionally,higher Mettl14 levels induced by exercise werepositively associated with browning markers in iWAT. Mettl14HET led to increased weight gain and fat accumulation in amechanism dependent on m6A levels. Furthermore, HET micedemonstrated notable reductions in oxygen consumption andenergy expenditure at baseline. m6A levels were notably reducedin the iWAT of exercise-induced HET mice, yet the associatedmetabolic impairment was significantly mitigated. Exercisesubstantially correlates with enhanced browning and metabolicimprovements by modulating m6A levels through Mettl14expression in iWAT. However, this pathway does not criticallyregulate exercise-induced browning and the enhancement ofwhole-body metabolism.