Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. Crtc2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in Crtc2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/Crtc2 and the induction of Sirt1 and Pparα. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/Crtc2 negatively regulates the Sirt1/Pparα/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions.
Bibliographical noteFunding Information:
We thank Professor Sung-Gil Chi (Korea University, Seoul, Korea) for pCMV-flag-p53 construct and Professor Jongsook Kim Kemper (University of Illinois, Champaign, IL, USA) for miR-34a adenovirus construct. We thank Professor Je Kyung Seong (Korea Mouse Phenotyping Center, Seoul National University, Seoul, Korea) for the help to utilize NMR analyzer Bruker Minispec LF50, and Professor Sung-Wook Chi (Korea University, Seoul, Korea) for the help to analyze AGO2-associated miR-34a. We also thank Sun Myung Park (Korea University, Seoul, Korea) for technical assistance and members of our laboratory for the critical reading of the manuscript. This work was supported by the National Research Foundation of Korea (grant nos.: NRF-2012M3A9B6055345, NRF-2015R1A5A1009024, NRF-2015R1A2A1A01006687, and NRF-2017M3A9D5A01052447), funded by the Ministry of Science and ICT, Republic of Korea, and a grant from Korea University, Seoul, Republic of Korea.
© 2017 The Author(s).
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)