title: A link between hepatic glucose production and peripheral energy metabolism via hepatokines.
abstract: Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France ; University of Aleppo, Aleppo, Syria.
authors: Aya
authors: A
authors: Abdul-Wahed
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Amandine
authors: A
authors: Gautier-Stein
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Sylvie
authors: S
authors: Casteras
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Maud
authors: M
authors: Soty
authors: Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France ; Centre National de la Recherche Scientifique, UMR5023, Villeurbanne, F-69622, France.
authors: Damien
authors: D
authors: Roussel
authors: Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France ; Centre National de la Recherche Scientifique, UMR5023, Villeurbanne, F-69622, France.
authors: Caroline
authors: C
authors: Romestaing
authors: INRA-ToxALim, Toulouse, F-31027, France.
authors: Hervé
authors: H
authors: Guillou
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Jean-André
authors: JA
authors: Tourette
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Nicolas
authors: N
authors: Pleche
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Carine
authors: C
authors: Zitoun
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Blandine
authors: B
authors: Gri
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Anne
authors: A
authors: Sardella
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Fabienne
authors: F
authors: Rajas
authors: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
authors: Gilles
authors: G
authors: Mithieux
keywords: Endogenous glucose production; Energy expenditure; Hepatokines; Liver; Obesity; Type 2 diabetes