Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease
K Watt, DC Henstridge, M Ziemann, CB Sim, MK Montgomery, D Samocha-Bonet, BL Parker, GT Dodd, ST Bond, TM Salmi, RS Lee, RE Thomson, A Hagg, JR Davey, H Qian, R Koopman, A El-Osta, JR Greenfield, MJ Watt, MA Febbraio Show all
NATURE COMMUNICATIONS | NATURE RESEARCH | Published : 2021
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 w..View full abstract
Awarded by National Heart Foundation of Australia Future Leader Fellowship
We thank Stephanie Jansen and Prue O'Hare, AMREP animal services, Melbourne for technical assistance. We acknowledge Dr Daniel Chan, Garvan Institute, Sydney who collected human muscle biopsies used in this study and express our gratitude to the subjects that participated in the studies that collected muscle biopsies. We acknowledge Metabolomics Australia for their contribution to this work. We also acknowledge the use of Illumina sequencing at the Australian Genome Research Facility and the Victorian Clinical Genetics Service (and the support they receive from the Commonwealth of Australia). Figure schematics were generated using BioRender (https://app.biorender.com/).This work was supported by a Project grant from the Australian National Health and Medical Research Council (NHMRC) (awarded to K.F.H. and P.G.) and a Diabetes Australia general grant (awarded to K.I.W.). P.G., A.E.O., M.J.W. and K.F.H. are supported by Senior Research Fellowships, M.A.F. by a Principal Research Fellowship and M.K.M. by a career development fellowship (all from the NHMRC). A.G.C. is supported by an Investigator grant from the NHMRC and a future fellowship from the Australian Research Council. B.G.D. is supported by a National Heart Foundation of Australia Future Leader Fellowship (101789). The University of Melbourne, Monash University, Deakin University, the Murdoch Children's Research Institute and the Baker Heart and Diabetes Institute are supported in part by the Operational Infrastructure Support Programme of the Victorian Government.