Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in diabetes and obesity

ABSTRACT: Non-coding RNAs from the Dlk1-Dio3 locus are critical for the maturation of metabolic tissues in early stages of postnatal development; however, their role in the mature organs remains elusive. Herein, we show that microRNAs from the miR-379/miR-410 cluster are robustly upregulated in livers of obese human subjects and various mouse models of metabolic dysfunction. Adult-onset, combinatorial inhibition of this miRNA cluster by hepatocyte-specific expression of a decoy sequence induced profound reductions in triglyceride, total and LDL cholesterol circulating levels, as well as decreased basal glycemia and improved glucose tolerance and insulin sensitivity. Consistent with the decoy-triggered enhancement of PI3K/mTOR signaling in these mice, hepatocytes expressing the combinatorial decoy showed augmented mitochondrial mass and function. Notably, decoy therapy led to vast improvements in glucose and lipid homeostasis in both type 1 diabetic and diet-induced, type 2 pre-diabetic, obese animals with no discernable side effects. Collectively, our results demonstrate that microRNAs from the miR-379/miR-410 cluster are critical regulators of metabolic homeostasis in the mature liver. Given the preservation of miRNA dysfunction in human obesity, combinatorial inhibition of an entire miRNA cluster by decoy-mediated targeting represents an unprecedented approach towards multi-parameter improvements in diabetes and obesity.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Juliane Merl-Pham  

LAB HEAD: Stephan Herzig

PROVIDER: PXD044478 | Pride | 2026-07-30

REPOSITORIES: Pride