Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

• Published in: Nature communications Vol. 12; no. 1; p. 2887
• Main Authors: Watt, K. I., Henstridge, D. C., Ziemann, M., Sim, C. B., Montgomery, M. K., Samocha-Bonet, D., Parker, B. L., Dodd, G. T., Bond, S. T., Salmi, T. M., Lee, R. S., Thomson, R. E., Hagg, A., Davey, J. R., Qian, H., Koopman, R., El-Osta, A., Greenfield, J. R., Watt, M. J., Febbraio, M. A., Drew, B. G., Cox, A. G., Porrello, E. R., Harvey, K. F., Gregorevic, P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/44; 13/51; 13/89; 38/77; 38/91; 631/443/319; 631/80; 64/60; 96/95; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adipose tissue; Adiposity - genetics; Animals; Diabetes mellitus; Energy expenditure; Fatty acids; Fatty Acids - metabolism; Gene Expression Regulation; Humanities and Social Sciences; Insulin; Insulin resistance; Insulin Resistance - genetics; Lipid metabolism; Lipids; Male; Metabolic Diseases - genetics; Metabolic Diseases - metabolism; Metabolic disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Obesity; Obesity - genetics; Obesity - metabolism; Oxidation; Oxidation-Reduction; Public health; Reverse Transcriptase Polymerase Chain Reaction - methods; Risk analysis; Risk factors; RNA Interference; Science; Science (multidisciplinary); Skeletal muscle; Substrates; Transcription; YAP-Signaling Proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23240-7

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese ( db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease. The mechanisms driving metabolic dysfunction in obesity remain incompletely understood. Here, the authors show that the levels of Hippo pathway effector YAP are reduced in muscle from individuals with insulin resistance and obese-diabetic mice, and that YAP promotes skeletal muscle lipid metabolism and limits adiposity in obese mice.