Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice.
BACKGROUND & AIMS
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.
['Peyrou|Marion|M|', 'Bourgoin|Lucie|L|', 'Poher|Anne-Laure|AL|', 'Altirriba|Jordi|J|', 'Maeder|Christine|C|', 'Caillon|Aurélie|A|', 'Fournier|Margot|M|', 'Montet|Xavier|X|', 'Rohner-Jeanrenaud|Françoise|F|', 'Foti|Michelangelo|M|']
D000273:Adipose Tissue D050154:Adiposity D000818:Animals D015153:Blotting, Western D002478:Cells, Cultured D005234:Fatty Liver D005786:Gene Expression Regulation D005947:Glucose D005951:Glucose Tolerance Test D007333:Insulin Resistance D050356:Lipid Metabolism D050155:Lipogenesis D008279:Magnetic Resonance Imaging D051379:Mice D018345:Mice, Knockout D051059:PTEN Phosphohydrolase D010641:Phenotype D012313:RNA D014057:Tomography, X-Ray Computed
Steatosis Glucose tolerance Beige adipocyte FGF21 Gluconeogenesis Organ crosstalk