Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of 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 subjects with obesity and various mouse models of metabolic dysfunction. Adult-onset, combinatorial inhibition of this miRNA cluster by hepatocyte-specific expression of a decoy sequence reduces triglyceride, total and LDL cholesterol circulating levels, decreases basal glycemia and improves glucose tolerance and insulin sensitivity irrespective of sex. Consistent with the decoy-triggered enhancement of PI3K/mTOR signaling in these mice, hepatocytes expressing the combinatorial decoy show augmented mitochondrial mass and function. Notably, decoy therapy also ameliorates glucose and lipid homeostasis in both type 1 diabetic and diet-induced, type 2 pre-diabetic, obese male animals. 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, hepatocyte-specific combinatorial inhibition of a large miRNA cluster represents an approach towards multi-parameter improvements in diabetes and obesity.
Authors
- Anja Zeigerer (ORCID: https://orcid.org/0000-0003-4072-0566)
- Manuel Gil‐Lozano (ORCID: https://orcid.org/0000-0002-2112-4243)
- Juliane Merl‐Pham (ORCID: https://orcid.org/0000-0002-3422-4083)
- 권윤 (ORCID: https://orcid.org/0000-0003-4847-3379)
- Katarina Klepac
- Daniela Hass
- Moya Wu
- Gretchen Wolff
- Maria Troullinaki
- Carolyn L. Cummins (ORCID: https://orcid.org/0000-0001-7603-6577)
- Annette Feuchtinger (ORCID: https://orcid.org/0000-0003-4324-2547)
- Juliano Machado (ORCID: https://orcid.org/0000-0001-8787-7144)
- Pauline Morigny (ORCID: https://orcid.org/0000-0002-8001-7069)
- N. Henriette Uhlenhaut (ORCID: https://orcid.org/0000-0002-4220-4779)
- Estefanía Simoes (ORCID: https://orcid.org/0000-0002-2842-5030)
- Tobias Wiedemann (ORCID: https://orcid.org/0000-0002-8101-7407)
- Stephan Herzig (ORCID: https://orcid.org/0000-0003-3950-3652)
- Matthias Blüher (ORCID: https://orcid.org/0000-0003-0208-2065)
- Maude Giroud (ORCID: https://orcid.org/0000-0001-6320-5546)
- Michael Buettner
- Adriano Maida (ORCID: https://orcid.org/0000-0002-2317-2484)
- Céline Jouffe (ORCID: https://orcid.org/0000-0002-7176-4724)
- Revathi Sekar (ORCID: https://orcid.org/0000-0002-6787-7742)
- Daniel Samaga (ORCID: https://orcid.org/0000-0001-7087-2208)
- Julia Szendroedi (ORCID: https://orcid.org/0000-0002-7296-7152)
- Marcos Rios Garcia
- Peter Weber
Institutions
- University of Toronto (CA)
- Universidade de Santiago de Compostela (ES)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Helmholtz Zentrum München (DE)
- German Centre for Cardiovascular Research (DE)
- Cancer Research UK Clinical Trials Unit (GB)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- University of Birmingham (GB)
- Leipzig University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-21
- DOI
- https://doi.org/10.1038/s41467-026-77808-2
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00