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Please use this identifier to cite or link to this item: https://wslhd.intersearch.com.au/wslhdjspui/handle/1/9019
TitleObesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation
Authors: Xia, W.;Veeragandham, P.;Cao, Y.;Xu, Y.;Rhyne, T. E.;Qian, J.;Hung, C. W.;Zhao, P.;Jones, Y.;Gao, H.;Liddle, Christopher;Yu, R. T.;Downes, M.;Evans, R. M.;Ryden, M.;Wabitsch, M.;Wang, Z.;Hakozaki, H.;Schoneberg, J.;Reilly, S. M.;Huang, J.;Saltiel, A. R.
WSLHD Author: Liddle, Christopher
Issue Date: 2024
Citation: Nature Metabolism 6(2):273-289, 2024
Abstract: Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction. Copyright 2024. The Author(s).
URI: https://wslhd.intersearch.com.au/wslhdjspui/handle/1/9019
DOI: https://dx.doi.org/10.1038/s42255-024-00978-0
Journal: Nature Metabolism
Type: Journal Article
Department: Storr Liver Centre
Facility: Westmead
Keywords: Animals
Insulin Resistance
Adipocytes, White
Obesity
Adipose Tissue
Weight Gain
Appears in Collections:Westmead Hospital 2019 - 2024

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