Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals

Sohei Tsukita; Tetsuya Yamada; Kenji Uno; Kei Takahashi; Keizo Kaneko; Yasushi Ishigaki; Junta Imai; Yutaka Hasegawa; Shojiro Sawada; Hisamitsu Ishihara; Yoshitomo Oka; Hideki Katagiri

doi:10.1016/j.cmet.2012.11.006

Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals

Sohei Tsukita, Tetsuya Yamada, Kenji Uno, Kei Takahashi, Keizo Kaneko, Yasushi Ishigaki, Junta Imai, Yutaka Hasegawa, Shojiro Sawada, Hisamitsu Ishihara, Yoshitomo Oka, Hideki Katagiri

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Abstract

Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.

Original language	English
Pages (from-to)	825-832
Number of pages	8
Journal	Cell Metabolism
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2012.11.006
Publication status	Published - 2012 Dec 5

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

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

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10.1016/j.cmet.2012.11.006

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title = "Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals",

abstract = "Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.",

author = "Sohei Tsukita and Tetsuya Yamada and Kenji Uno and Kei Takahashi and Keizo Kaneko and Yasushi Ishigaki and Junta Imai and Yutaka Hasegawa and Shojiro Sawada and Hisamitsu Ishihara and Yoshitomo Oka and Hideki Katagiri",

note = "Funding Information: We thank M. Hoshi, T. Takasugi, J. Fushimi, and R. Tomono for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (to T.Y. and H.K.) from the Japan Society for the Promotion of Science. This work was also supported by a Grant-in-Aid for Scientific Research on Innovative Areas (to H.K.) and the Global-COE (H.K. and Y.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. ",

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AU - Tsukita, Sohei

AU - Yamada, Tetsuya

AU - Uno, Kenji

AU - Takahashi, Kei

AU - Kaneko, Keizo

AU - Ishigaki, Yasushi

AU - Imai, Junta

AU - Hasegawa, Yutaka

AU - Sawada, Shojiro

AU - Ishihara, Hisamitsu

AU - Oka, Yoshitomo

AU - Katagiri, Hideki

N1 - Funding Information: We thank M. Hoshi, T. Takasugi, J. Fushimi, and R. Tomono for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (to T.Y. and H.K.) from the Japan Society for the Promotion of Science. This work was also supported by a Grant-in-Aid for Scientific Research on Innovative Areas (to H.K.) and the Global-COE (H.K. and Y.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

PY - 2012/12/5

Y1 - 2012/12/5

N2 - Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.

AB - Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.

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Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals

Abstract

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UN SDGs

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