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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Bioscientifica
2025-06-01
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| Series: | Endocrine Connections |
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| Online Access: | https://ec.bioscientifica.com/view/journals/ec/14/6/EC-25-0028.xml |
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| author | Shuang Guo Mengnan Lu Yuesheng Liu Hongai Zhang Biyao Lian Yanfeng Xiao Chunyan Yin |
| author_facet | Shuang Guo Mengnan Lu Yuesheng Liu Hongai Zhang Biyao Lian Yanfeng Xiao Chunyan Yin |
| author_sort | Shuang Guo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-545c4e4b57f34f6ca43557280c2cda89 |
| institution | DOAJ |
| issn | 2049-3614 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | Endocrine Connections |
| spelling | doaj-art-545c4e4b57f34f6ca43557280c2cda892025-08-20T03:10:49ZengBioscientificaEndocrine Connections2049-36142025-06-0114610.1530/EC-25-00281lncRNA RP11-34D15.2 sponges miR-223 to promote the PGC-1α/irisin signaling pathway, contributing to increased FFA and insulin resistance in obese childrenShuang Guo0Mengnan Lu1Yuesheng Liu2Hongai Zhang3Biyao Lian4Yanfeng Xiao5Chunyan Yin6Department of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaDepartment of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaDepartment of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaDepartment of Neonatology, Shanghai General Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaDepartment of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaDepartment of Pediatrics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, ChinaBackground: 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.https://ec.bioscientifica.com/view/journals/ec/14/6/EC-25-0028.xmlinsulin resistancelncrna rp11-34d15.2mir-223free fatty acidspediatric obesity |
| spellingShingle | Shuang Guo Mengnan Lu Yuesheng Liu Hongai Zhang Biyao Lian Yanfeng Xiao Chunyan Yin 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 Endocrine Connections insulin resistance lncrna rp11-34d15.2 mir-223 free fatty acids pediatric obesity |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | insulin resistance lncrna rp11-34d15.2 mir-223 free fatty acids pediatric obesity |
| url | https://ec.bioscientifica.com/view/journals/ec/14/6/EC-25-0028.xml |
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