American Diabetes Association
Supplementary_Figures_Tables_and_Methods_Park_2024_0415_R2_5.pdf (1002.24 kB)

Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance

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posted on 2024-04-24, 14:57 authored by Soyoung Park, Hye-Na Cha, Min-Gyeong Shin, Sanghee Park, Yeongmin Kim, Min-Seob Kim, Kyung-Hoon Shin, Themis Thoudam, Eun Ju Lee, Robert R. Wolfe, Jinmyoung Dan, Jin-Ho Koh, Il-Young Kim, Inho Choi, In-kyu Lee, Hoon-Ki Sung, So-Young Park

Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.


S.-Y.P is supported by the Medical Research Center Program (2022R1A5A2018865) and the Basic Science Research Program (2019R1A2C1088730) through the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Science and ICT (MSIT). I.-Y. K. is supported by the NRF funded by the Korean MSIT (2021R1A2C3005801). M.-S.K is supported by the National Institute of Environment Research (2021-01-01-097).


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