Figure 9.

Hepatocyte-selective TFEB knockdown attenuates trehalose-induced thermogenesis in vivo. (A) Hepatic Tfeb mRNA abundance in Tfeb shRNA-treated mice (2 wk) treated with or without 5-day 3% trehalose water (n = 4–8 mice per group). (B) Interscapular brown adipose tissue (iBAT) and epididymal white adipose tissue (eWAT) expression of Tfeb in mice treated with AAV8 encoding Tfeb shRNA or empty vector with or without trehalose treatment. (C) eWAT Ppargc1a and Ucp1 mRNA abundance in response to AAV8-mediated Tfeb shRNA delivery and 5-day trehalose treatment. (D-F). Heat production (D), oxygen consumption (E), and CO₂ production (F) in mice infected with AAV8 encoding empty vector or Tfeb-directed shRNA following treatment with sterile water or trehalose (5 days). (G) Circulating FGF21 peptide quantification by colorimetric ELISA in serum from mice treated with or without trehalose and with or without Tfeb-directed shRNA. (H) Working model of trehalose-induced thermogenesis. Trehalose induces hepatic fasting responses via TFEB and PPARGC1A to enhance FGF21 and downstream UCP1 in the hepatocyte and in eWAT. Autophagy appears to act independent of this thermogenic pathway. * P < 0.05, ** P < 0.01, **** P < 0.0001 by Student’s T-test with Bonferroni-Dunn post-hoc correction for multiple tests.