title: The suppression of hepatic glucose production improves metabolism and insulin sensitivity in subcutaneous adipose tissue in mice.
abstract: Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals.
  
  
  
  Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L-G6pc-/-mice). Morphological and metabolic changes in the adipose tissues were characterised by histological analyses, gene expression and protein content.
  
  
  
  Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver.
  
  
  
  Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Casteras
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Aya
authors.initials: A
authors.lastname: Abdul-Wahed
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Soty
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Vulin
authors.affiliation: INRA, ToxAlim UMR1331 (Research Center in Food Toxicology), Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: Unité Biologie Fonctionnelle et Adaptative -UMR CNRS 8251, Université Paris- Diderot (7), Paris, France.|I2BC - UMR 9198 Université Paris Sud, Gif sur Yvette, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Campana
authors.affiliation: Unité Biologie Fonctionnelle et Adaptative -UMR CNRS 8251, Université Paris- Diderot (7), Paris, France.|I2BC - UMR 9198 Université Paris Sud, Gif sur Yvette, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
authors.affiliation: Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.|Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition, CarMeN, Oullins, France.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pirola
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rajas
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France.|Université de Lyon, Lyon, France.|Université Lyon1, Villeurbanne, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
authors.affiliation: Inserm U1213, Faculté Laennec, 7 rue Guillaume Paradin, 69372, Lyon cedex 08, France. amandine.gautier-stein@univ-lyon1.fr.|Université de Lyon, Lyon, France. amandine.gautier-stein@univ-lyon1.fr.|Université Lyon1, Villeurbanne, France. amandine.gautier-stein@univ-lyon1.fr.
authors.forename: Amandine
authors.initials: A
authors.lastname: Gautier-Stein
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050178:Monoglycerides / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism
chemical_list: D007328:Insulin; D050178:Monoglycerides; D005947:Glucose
keywords: Adipose tissue; Fatty acids; Glucose 6-phosphatase; Hepatic glucose production; Hepatokines; Insulin resistance; Liver; Obesity; Steatosis