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Herein, we show that microRNAs from the\n                    <jats:italic>miR-379\/miR-410<\/jats:italic>\n                    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\n                    <jats:italic>miR-379\/miR-410<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-77808-2","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:24:56Z","timestamp":1789979096000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial targeting of the miR-379\/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity"],"prefix":"10.1038","volume":"17","author":[{"given":"Manuel","family":"Gil-Lozano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefan\u00eda","family":"Simoes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moya","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-7407","authenticated-orcid":false,"given":"Tobias","family":"Wiedemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revathi","family":"Sekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8001-7069","authenticated-orcid":false,"given":"Pauline","family":"Morigny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Troullinaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-4083","authenticated-orcid":false,"given":"Juliane","family":"Merl-Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Buettner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Feuchtinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7176-4724","authenticated-orcid":false,"given":"Celine","family":"Jouffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano","family":"Maida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Hass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Samaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliano","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maude","family":"Giroud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Klepac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-6577","authenticated-orcid":false,"given":"Carolyn L.","family":"Cummins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"R\u00edos Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4072-0566","authenticated-orcid":false,"given":"Anja","family":"Zeigerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4220-4779","authenticated-orcid":false,"given":"N. 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