Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs.

ABSTRACT: Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects obs

SUBMITTER: Liko D 

PROVIDER: S-EPMC6983401 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature