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

K. I. Watt, D. C. Henstridge, M. Ziemann, C. B. Sim, M. K. Montgomery, D. Samocha-Bonet, B. L. Parker, G. T. Dodd, S. T. Bond, T. M. Salmi, R. S. Lee, R. E. Thomson, A. Hagg, J. R. Davey, H. Qian, R. Koopman, A. El-Osta, J. R. Greenfield, M. J. Watt, M. A. Febbraio, B. G. Drew, A. G. Cox, E. R. Porrello, K. F. Harvey and P. Gregorevic ()
Additional contact information
K. I. Watt: The University of Melbourne
D. C. Henstridge: University of Tasmania
M. Ziemann: Deakin University
C. B. Sim: Murdoch Children’s Research Institute
M. K. Montgomery: The University of Melbourne
D. Samocha-Bonet: Garvan Institute of Medical Research
B. L. Parker: The University of Melbourne
G. T. Dodd: The University of Melbourne
S. T. Bond: Baker Heart and Diabetes Institute
T. M. Salmi: Peter MacCallum Cancer Centre
R. S. Lee: Monash University
R. E. Thomson: The University of Melbourne
A. Hagg: The University of Melbourne
J. R. Davey: The University of Melbourne
H. Qian: The University of Melbourne
R. Koopman: The University of Melbourne
A. El-Osta: Monash University
J. R. Greenfield: Garvan Institute of Medical Research
M. J. Watt: The University of Melbourne
M. A. Febbraio: Monash University
B. G. Drew: Baker Heart and Diabetes Institute
A. G. Cox: Peter MacCallum Cancer Centre
E. R. Porrello: The University of Melbourne
K. F. Harvey: Peter MacCallum Cancer Centre
P. Gregorevic: The University of Melbourne

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23240-7

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