title: Histidine augments the suppression of hepatic glucose production by central insulin action.
abstract: Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Asahara
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Akifumi
authors.initials: A
authors.lastname: Maeda
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Inagaki
authors.forename: Chisato
authors.initials: C
authors.lastname: Mukai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakabayashi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000818:Animals; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000096:biosynthesis*; D006639:Histidine / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D007328:Insulin; D011969:Receptors, Histamine H1; D050796:STAT3 Transcription Factor; D006639:Histidine; D011972:Receptor, Insulin; D005947:Glucose