Skeletal muscle adapts to nutrient availability and physiological demands by fine-tuning gene expression patterns and metabolism to maximize metabolic efficiency. The mechanisms that enable and mediate muscle transcriptional and metabolic responses to environmental cues remain unclear, however. We have shown previously that enhancer regulator MLL4 is required for establishing and maintaining slow type I fiber program to ensure running endurance (J Clin Invest. 2020;130(9):4710-4725). Here, we report that MLL4 plays a critical role in directing muscle metabolic transcriptional adaptation that governs metabolic efficiency and systemic metabolism. MLL4 expression is regulated by nutrient availability, and skeletal muscle-specific ablation of MLL4 protects mice against diet-induced obesity and improves systemic glucose homeostasis despite reducing exercise endurance. Combining comprehensive metabolic and genomic analysis of the MLL4-depleted muscles using multidimensional ‘omics’ technologies, we gained insight into the molecular targets and biological functions of the MLL4 protein. Specifically, this seemingly paradoxical phenotype is due to markedly enhanced fuel catabolism in MLL4 deficient muscles, a favorable metabolic reprogramming caused by the activation of muscle AMPK. Isotopic 13C-glucose tracing experiments in myocyte provided further evidence that MLL4 exerts control upon muscle fuel catabolism. Remarkably, pharmacologic targeting the MLL4 pathway activates muscle AMPK, confers resistance to diet-induced obesity and ameliorates obesity-related insulin resistance and liver steatosis. These results identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism and offer a new potential therapeutic strategy for obesity-related metabolic disorders.


L.Yang: None. L.Liu: None. C.Ding: None. T.Fu: None. Z.Zhou: None. Z.Gan: None.

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