Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Abstract

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.

The suppression of hepatic glucose production improves metabolism and insulin sensitivity in subcutaneous adipose tissue in mice

“…It is of note that all mouse models exhibiting a dissociation between hepatic steatosis and insulin resistance are characterised by an increase in hepatic FGF21 levels and MUFA/SFA ratio, and are never associated with an increase in HGP [2,3,6]. The latter observation reinforces the key role of increased HGP in the appearance of fasting hyperglycaemia …”

“…However, recent studies have demonstrated that triacylglycerol accumulation in the liver can be associated with improved insulin sensitivity, due to better glucose control in the peripheral tissues [2,3,6,24,25]. To further document the mechanisms involved in this interorgan communication, we studied whether liver metabolism might control insulin signalling in the peripheral tissues.…”

“…It is noteworthy that specific mechanisms, for example related to hepatokines, can dissociate hepatic steatosis from insulin resistance. For example, fetuin A (a hepatokine associated with steatosis and deleterious glucose control) is decreased in insulin-sensitive steatosis of liver-specific PTEN (phosphatase and tensin homolog) knockout mice [2]. Conversely, the increased production of fibroblast growth factor 21 (FGF21) is associated with insulin-sensitive steatosis [2][3][4].…”

“…For example, fetuin A (a hepatokine associated with steatosis and deleterious glucose control) is decreased in insulin-sensitive steatosis of liver-specific PTEN (phosphatase and tensin homolog) knockout mice [2]. Conversely, the increased production of fibroblast growth factor 21 (FGF21) is associated with insulin-sensitive steatosis [2][3][4]. Similarly, changes in lipid metabolism in the liver are sometimes associated with peripheral insulin sensitivity [5,6].…”

Breaking BAT: can browning create a better white?

“…Consequently, the inhibition of these pathways in turn leads to the appearance of beige adipocytes. This includes peripheral serotonin levels (Crane et al 2015), the TGFb/SMAD3/myostatin cascade (Shan et al 2013, hepatic PTEN (Peyrou et al 2015), Notch or prolactin receptor signaling (Auffret et al 2012, Bi et al 2014, as well as Cox2 (Madsen et al 2010).…”