WRN loss accelerates abnormal adipocyte metabolism in Werner syndrome

Author:

Tian Yuyao,Lautrup Sofie,Law Patrick Wai Nok,Dinh Ngoc-Duy,Fang Evandro Fei,Chan Wai-YeeORCID

Abstract

Abstract Background Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage. Methods In an in vivo study, we generated wrn−/− mutant zebrafish and performed histological stain and Oil Red O staining to assess the fat metabolism. In an in vitro study, we used RNA-seq and ATAC-seq to profile the transcriptional features and chromatin accessibility in WRN depleted adipocytes. Moreover, we performed ChIP-seq to further study the regulatory mechanisms of metabolic dysfunction in WS. Results Our findings show that mechanistically WRN deficiency causes SMARCA5 upregulation. SMARCA5 is crucial in chromatin remodeling and gene regulation. Additionally, rescuing WRN could normalize SMARCA5 expression and adipocyte differentiation. Moreover, we find that nicotinamide riboside (NR) supplementation restores adipocyte metabolism in both stem cells and zebrafish models. Conclusions Our findings unravel a new mechanism for the influence of WRN in the early stage of adipogenesis and provide a possible treatment for metabolic dysfunction in WS. These data provide promising insights into potential therapeutics for ageing and ageing-related diseases.

Funder

VC Discretionary Fund provided to the Hong Kong Branch of Chinese Academy of Science Center for Excellence in Animal Evolution and Genetics

State Ministries Special Budget to support MOE Key Laboratory for Regenerative Medicine

Shandong University-Chinese University of Hong Kong Seed Fund for International Research Collaboration

Cure Alzheimer’s Fund,HELSE SØR-ØST

the Research Council of Norway

Molecule AG/VITADAO

NordForsk Foundation

Marie Skłodowska-Curie grant

Publisher

Springer Science and Business Media LLC

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