Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepatic steatosis
Abstract
Up to a third of the global population is afflicted by metabolic dysfunction-associated steatotic liver disease with excessive triglyceride accumulation in the liver. Prolonged fasting rapidly causes hepatic steatosis via excessive influx of free fatty acids from adipose tissue. However, it is unclear whether skeletal muscle is involved in the etiology of hepatic steatosis during starvation. Here, we demonstrate a critical connection between the liver and skeletal muscle via FoxO transcription factors. During prolonged fasting, hepatic steatosis was exacerbated in skeletal muscle–specific FoxO-deficient mice (mFoxO1,3,4 −/− ) despite preventing skeletal muscle wasting, suggesting that skeletal muscle FoxOs prevent hepatic steatosis during energy deprivation. FoxO deficiency in skeletal muscle weakened fatty acid oxidation and induced abnormal glycogen accumulation in skeletal muscle during fasting. Mechanistically, the starvation-induced transcriptional regulation of triglyceride lipase was attenuated in skeletal muscle of FoxO-deficient mice. Conversely, skeletal muscle–specific FOXO1 overexpression was sufficient to increase triglyceride lipase in vivo and protected the liver from Western diet–induced metabolic dysfunction–associated steatohepatitis-like phenotype. Taken together, our results demonstrate the physiological importance of skeletal muscle FoxO signaling on the liver pathophysiology.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Mamoru Oyabu
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Manato Sakaue
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Atsushi Kubo
Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka
Kiyoshi Yoshioka
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Runa Kawaguchi
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Haruki Yamamoto
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Yuzuka Kinjo
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
Jungin Kwon
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
Hiroki Nishi
Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo
Daisuke Yamanaka
Department of Veterinary Medical Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo
Tomoki Sato
Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka
Daiki Mori
Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka
Takahiro Eguchi
Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology
Naoki Ito
Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology
So-ichiro Fukada
Takayoshi Suganami
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University
Shinji Miura
Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka
Yusuke Ono
Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics, Kumamoto University
Fumihiko Hakuno
Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo
Shin-ichiro Takahashi
Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo
Tsuyoshi Goto
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
Yasutomi Kamei
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University