lncRNA RP11-34D15.2 sponges miR-223 to promote the PGC-1α/irisin signaling pathway, contributing to increased FFA and insulin resistance in obese children
Background: The global surge in pediatric obesity is closely linked to insulin resistance (IR) and type 2 diabetes, where adipose tissue free fatty acid (FFA) overload and mitochondrial dysfunction play pivotal roles. Long non-coding RNAs (lncRNAs) are emerging regulators of metabolic diseases, but...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Bioscientifica
2025-06-01
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| Series: | Endocrine Connections |
| Subjects: | |
| Online Access: | https://ec.bioscientifica.com/view/journals/ec/14/6/EC-25-0028.xml |
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| Summary: | Background: The global surge in pediatric obesity is closely linked to insulin resistance (IR) and type 2 diabetes, where adipose tissue free fatty acid (FFA) overload and mitochondrial dysfunction play pivotal roles. Long non-coding RNAs (lncRNAs) are emerging regulators of metabolic diseases, but their mechanistic contributions to childhood obesity-associated IR remain underexplored. Objective: This study investigates whether lncRNA RP11-34D15.2 modulates FFA-induced IR through the miR-223/PGC-1α/irisin signaling axis in obese children. Methods: We analyzed serum FFA, insulin, irisin, and white adipose tissue (WAT) transcriptomes in 40 obese and 40 normal-weight children. Functional validation included dual-luciferase reporter assays, primary adipocyte models, and high-fat diet (HFD) mice treated with lncRNA-specific shRNA (n = 10 per group). Molecular interactions were verified via RNA immunoprecipitation and western blotting. Results: Obese children exhibited 2.1-fold higher FFA levels and HOMA-IR (P < 0.01), but 38% lower serum irisin compared to controls, with irisin inversely correlating with body fat percentage (r = −0.67, P = 0.003). lncRNA RP11-34D15.2 was downregulated by 4.3-fold in obese WAT and positively correlated with irisin expression (r = 0.603, P = 0.018). Mechanistic studies revealed that lncRNA directly binds miR-223 (RIP-seq fold enrichment = 5.2, P = 0.004), relieving miR-223-mediated suppression of PGC-1α. Overexpressing lncRNA in adipocytes increased PGC-1α (2.8-fold) and irisin (1.9-fold), upregulated mitochondrial genes (CPT-1: 3.1-fold; UCP-1: 2.4-fold, P < 0.01), and reduced extracellular FFA by 44%. In HFD mice, lncRNA knockdown exacerbated glucose intolerance (AUC increased 29%, P = 0.007), whereas irisin supplementation restored insulin sensitivity (P = 0.013). Conclusion: lncRNA RP11-34D15.2 functions as a ceRNA sponging miR-223 to activate PGC-1α/irisin-mediated mitochondrial β-oxidation and FFA clearance, identifying therapeutic targets for childhood obesity. |
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| ISSN: | 2049-3614 |