title: Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice.
abstract: OBJECTIVE
  PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases.
  
  
  METHODS
  Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo.
  
  
  RESULTS
  PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice.
  
  
  CONCLUSIONS
  Although steatosis develops in LPTEN KO mice, PTEN deficiency in hepatocytes promotes a crosstalk between liver and muscle, as well as adipose tissue, resulting in enhanced insulin sensitivity, improved glucose tolerance and decreased adiposity.
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Peyrou
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Bourgoin
authors.affiliation: Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Poher
authors.affiliation: Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Jordi
authors.initials: J
authors.lastname: Altirriba
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Maeder
authors.affiliation: Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caillon
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Department of Radiology, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montet
authors.affiliation: Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rohner-Jeanrenaud
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland. Electronic address: Michelangelo.foti@unige.ch.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Foti
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005234:Fatty Liver / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D014057:Tomography, X-Ray Computed
chemical_list: D012313:RNA; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose
keywords: Beige adipocyte; FGF21; Gluconeogenesis; Glucose tolerance; Organ crosstalk; Steatosis