Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

Lixiang Wang; Takaya Ishihara; Yuta Ibayashi; Keita Tatsushima; Daiki Setoyama; Yuki Hanada; Yukina Takeichi; Shohei Sakamoto; Sadaki Yokota; Katsuyoshi Mihara; Dongchon Kang; Naotada Ishihara; Ryoichi Takayanagi; Masatoshi Nomura

doi:10.1007/s00125-015-3704-7

Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

Lixiang Wang, Takaya Ishihara, Yuta Ibayashi, Keita Tatsushima, Daiki Setoyama, Yuki Hanada, Yukina Takeichi, Shohei Sakamoto, Sadaki Yokota, Katsuyoshi Mihara, Dongchon Kang, Naotada Ishihara, Ryoichi Takayanagi, Masatoshi Nomura

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Abstract

Aim/hypothesis: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. Methods: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Results: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Conclusions/interpretation: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

Original language	English
Pages (from-to)	2371-2380
Number of pages	10
Journal	Diabetologia
Volume	58
Issue number	10
DOIs	https://doi.org/10.1007/s00125-015-3704-7
Publication status	Published - Oct 24 2015

All Science Journal Classification (ASJC) codes

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-015-3704-7

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Wang, L., Ishihara, T., Ibayashi, Y., Tatsushima, K., Setoyama, D., Hanada, Y., Takeichi, Y., Sakamoto, S., Yokota, S., Mihara, K., Kang, D., Ishihara, N., Takayanagi, R., & Nomura, M. (2015). Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia, 58(10), 2371-2380. https://doi.org/10.1007/s00125-015-3704-7

Wang, L, Ishihara, T, Ibayashi, Y, Tatsushima, K, Setoyama, D, Hanada, Y, Takeichi, Y, Sakamoto, S, Yokota, S, Mihara, K, Kang, D, Ishihara, N, Takayanagi, R & Nomura, M 2015, 'Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration', Diabetologia, vol. 58, no. 10, pp. 2371-2380. https://doi.org/10.1007/s00125-015-3704-7

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title = "Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration",

abstract = "Aim/hypothesis: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. Methods: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Results: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Conclusions/interpretation: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.",

author = "Lixiang Wang and Takaya Ishihara and Yuta Ibayashi and Keita Tatsushima and Daiki Setoyama and Yuki Hanada and Yukina Takeichi and Shohei Sakamoto and Sadaki Yokota and Katsuyoshi Mihara and Dongchon Kang and Naotada Ishihara and Ryoichi Takayanagi and Masatoshi Nomura",

note = "Funding Information: This work was supported in part by the Japanese Society for the Promotion of Science (JSPS) KAKENHI (MN, Grant no. 26461383, 12F02426; RT, Grant no. 23390247) and Grants-in-Aid for Research Fellowship for Young Science Foundation and Banyu Science Foundation (LW). The work of MN was supported by a grant from the Medical Research Encouragement Prize of The Japan Medical Association. Publisher Copyright: {\textcopyright} 2015, Springer-Verlag Berlin Heidelberg.",

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doi = "10.1007/s00125-015-3704-7",

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volume = "58",

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T1 - Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

AU - Wang, Lixiang

AU - Ishihara, Takaya

AU - Ibayashi, Yuta

AU - Tatsushima, Keita

AU - Setoyama, Daiki

AU - Hanada, Yuki

AU - Takeichi, Yukina

AU - Sakamoto, Shohei

AU - Yokota, Sadaki

AU - Mihara, Katsuyoshi

AU - Kang, Dongchon

AU - Ishihara, Naotada

AU - Takayanagi, Ryoichi

AU - Nomura, Masatoshi

N1 - Funding Information: This work was supported in part by the Japanese Society for the Promotion of Science (JSPS) KAKENHI (MN, Grant no. 26461383, 12F02426; RT, Grant no. 23390247) and Grants-in-Aid for Research Fellowship for Young Science Foundation and Banyu Science Foundation (LW). The work of MN was supported by a grant from the Medical Research Encouragement Prize of The Japan Medical Association. Publisher Copyright: © 2015, Springer-Verlag Berlin Heidelberg.

PY - 2015/10/24

Y1 - 2015/10/24

N2 - Aim/hypothesis: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. Methods: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Results: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Conclusions/interpretation: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

AB - Aim/hypothesis: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. Methods: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Results: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Conclusions/interpretation: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

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Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

Abstract

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