TFEB-dependent Induction of Thermogenesis by the Hepatocyte SLC2A Inhibitor Trehalose.

TFEB-dependent Induction of Thermogenesis by the Hepatocyte SLC2A Inhibitor Trehalose. Autophagy. 2018 Jul 12;: Authors: Zhang Y, Higgins CB, Mayer AL, Mysorekar IU, Razani BB, Graham MJ, Hruz PW, DeBosch BJ Abstract The macroautophagy/autophagy-inducing disaccharide, trehalose, has been proposed to be a promising therapeutic agent against neurodegenerative and cardiometabolic diseases. We recently showed that trehalose attenuates hepatic steatosis in part by blocking hepatocyte glucose transport to induce hepatocyte autophagic flux. However, although every major demonstration of trehalose action invokes activating autophagic flux as its primary function, the mechanism of action of trehalose in whole-body energy metabolism remains poorly defined. Here, we demonstrate that trehalose induces hepatocyte TFEB (transcription factor EB)-dependent thermogenesis in vivo, concomitant with upregulation of hepatic and white adipose expression of UCP1 (uncoupling protein 1 [mitochondrial, protein carrier]). Mechanistically, we provide evidence that hepatocyte fasting transcriptional and metabolic responses depend upon PPARGC1A (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha), TFEB, and FGF21 (fibroblast growth factor 21) signaling. Strikingly, hepatocyte-selective TFEB knockdown abrogated trehalose induction of thermogenesis and white adipose tissue UCP1 upregulation in vivo. In contrast, we found that trehalose action o...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research