MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38745315", "kind": "science-record", "revision": 5, "content_hash": "sha256:df18d9c88e4156fbc80ee0e63843b61f20fc1ceedc33efac72d8f9329ec241ba", "created_at": "2026-11-01T19:20:42Z", "updated_at": "2026-11-01T22:54:18Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.", "doi": "10.1186/s40659-024-00495-0", "pmid": "38745315", "authors": ["Shaheen Wasil Kabeer", "Shivam Sharma", "Shalemraju Sriramdasu", "Kulbhushan Tikoo"], "journal": "Biological research", "year": 2024, "abstract": "BACKGROUND: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance.\nRESULTS: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis.\nCONCLUSION: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.", "claims": [{"id": "claim-method", "statement": "Two-tailed Student's t-test was applied to compare means of two groups. In cases where multiple groups were compared, one-way analysis of variance (ANOVA) was used and Tukey's test was employed for post-hoc analysis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38745315", "locator": "sections[15] \"Statistical analysis\" paragraph 2", "quote": "Two-tailed Student's t-test was applied to compare means of two groups. In cases where multiple groups were compared, one-way analysis of variance (ANOVA) was used and Tukey's test was employed for post-hoc analysis."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All the data described in this study is contained within the article.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38745315", "locator": "sections[32] \"notes\" paragraph 1", "quote": "All the data described in this study is contained within the article."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38745315", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38745315"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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