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

Kevin I Watt ,R S Lee,Mark Ziemann ,Magdalene K Montgomery ,Darren C Henstridge ,Adam Hagg ,Jonathan R Davey ,Mark A Febbraio ,Assam El‐Osta ,Enzo R Porrello ,Simon T Bond ,Russell Thomson ,Hongwei Qian ,Ben L Parker ,René Koopman ,Garron T Dodd ,Dorit Samocha-Bonet ,Matthew J Watt ,Choon Boon Sim ,Brian G Drew ,Jerry R Greenfield ,Kieran F Harvey ,Andrew G Cox ,Talhah M Salmi ,Paul Gregorevic

doi:10.1038/s41467-021-23240-7

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.

Highlights

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally
Consistent with the hypothesis that YAP functions as a positive mediator of metabolism in skeletal muscle, we found that YAP protein levels were reduced in the muscles of obese, insulin-resistant individuals compared to obese, insulin-sensitive individuals (Fig. 1B, Supplementary Fig. 1A)
We identified a positive correlation between YAP levels in human muscle biopsies and the glucose infusion rate relative to fat free mass (FFM) during a hyperinsulinemic-euglycemic clamp; a gold standard measure of skeletal muscle insulin sensitivity (Fig. 1C)

Summary

Introduction

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Changes in Hippo pathway activity have been reported in muscles undergoing atrophy associated with aging, disruption of the neuromuscular junction, or corticosteroid administration, and in muscles undergoing hypertrophy associated with increased loading[18,19,20,23,24] Combined, these observations identify the transcriptional regulators Yap and Taz as important post-natal effectors of skeletal muscle biology in health and disease, yet the biological processes controlled by the Hippo pathway in skeletal muscle remain unclear. Increasing Yap levels in the muscles of obese db/db mice attenuates adiposity by increased energy expenditure, independent of changes in lean mass, food intake or activity These findings provide evidence for an important role of the Hippo pathway as a postnatal regulator of metabolism in skeletal musculature

Methods

Results

Conclusion