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.
authors.affiliation: Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Tsukita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.forename: Keizo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics*; D015854:Up-Regulation; D015430:Weight Gain
chemical_list: D020738:Leptin; D034741:RNA, Small Interfering; D006003:Glycogen; D005941:Glucokinase