TFEB-dependent induction of thermogenesis by the hepatocyte SLC2A inhibitor trehalose

• Published in: Autophagy Vol. 14; no. 11; pp. 1959 - 1975
• Main Authors: Zhang, Yiming, Higgins, Cassandra B., Mayer, Allyson L., Mysorekar, Indira U., Razani, Babak, Graham, Mark J., Hruz, Paul W., DeBosch, Brian J.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.11.2018
• Subjects: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - physiology; Beclin 1; Cells, Cultured; ectopic P-granules autophagy protein; Energy Metabolism - drug effects; Energy Metabolism - genetics; fibroblast growth factor; glucose transport; Glucose Transport Proteins, Facilitative - antagonists & inhibitors; Glucose Transport Proteins, Facilitative - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Research Paper - Basic Science; solute carrier 2A; Thermogenesis - drug effects; Thermogenesis - genetics; transcription factor EB; Trehalose - pharmacology; Up-Regulation - drug effects; Up-Regulation - genetics; glucose transport; ectopic P-granules autophagy protein; solute carrier 2A; transcription factor EB; fibroblast growth factor; Beclin 1
• ISSN: 1554-8627; 1554-8635; 1554-8635
• DOI: 10.1080/15548627.2018.1493044

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 on thermogenesis was independent of LEP (leptin) and the autophagy pathway, as there was robust thermogenic induction in trehalose-treated ob/ob, Becn1, Atg16l1, and Epg5 mutant mice. We conclude that trehalose induces metabolically favorable effects on whole-body thermogenesis in part via hepatocyte-centered fasting-like mechanisms that appear to be independent of autophagic flux. Our findings elucidate a novel mechanism by which trehalose acts as a metabolic therapeutic agent by activating hepatic fasting responses. More broadly, the hepatic glucose fasting response may be of clinical utility against overnutrition-driven disease, such as obesity and type 2 diabetes mellitus.