Fig. 4.

Effect of miR-34a on adiposity is reversed by co-expression of Fgf21 in Crtc2 liver-specific knockout mice. a–d Effects of miR-34a and/or Fgf21 on Crtc2 ^LKO mice under 9-week HFD (n = 5 mice per group). Schematics of AAV injection (a, top) and the effect of miR-34a and Fgf21 on fat size (a, bottom) were shown. H&E staining of the liver, scWAT, visWAT, BAT of each group of mice were shown (b). c Western blot analysis showing hepatic protein levels, as well as Ucp1 protein levels in scWAT and BAT of each genotype. Data represent four independent experiments (n = 4 mice per group). Note that the HFD was initiated at 4 weeks of age and maintained throughout the experimental period. d Schematic diagram showing the effects of Creb/Crtc2-driven expression of miR-34a on hepatic fatty acid metabolism and whole-body energy homeostasis under diet-induced obesity (DIO) and insulin-resistant conditions. Depletion of Crtc2 promotes the activation of Sirt1/Pparα pathway under DIO conditions, leading to the increased hepatic fatty acid beta oxidation and the amelioration of fatty liver symptoms. In addition, enhanced hepatic Fgf21 expression is also essential in improving lipid metabolism in the peripheral tissues including the liver and adipose tissues, resulting in the increased energy expenditure and the improved insulin sensitivity