Guo Shuang, Lu Mengnan, Liu Yuesheng, Zhang Hongai, Lian Biyao, Xiao Yanfeng, Yin Chunyan
Endocr Connect. 2025 Jun 10;14(6). doi: 10.1530/EC-25-0028. Print 2025 Jun 1.
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.
This study investigates whether lncRNA RP11-34D15.2 modulates FFA-induced IR through the miR-223/PGC-1α/irisin signaling axis in obese children.
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.
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).
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.
全球儿童肥胖率的激增与胰岛素抵抗（IR）和2型糖尿病密切相关，其中脂肪组织游离脂肪酸（FFA）过载和线粒体功能障碍起着关键作用。长链非编码RNA（lncRNA）是代谢疾病中新兴的调节因子，但其对儿童肥胖相关IR的作用机制仍未得到充分研究。
本研究调查lncRNA RP11-34D15.2是否通过miR-223/PGC-1α/鸢尾素信号轴调节肥胖儿童中FFA诱导的IR。
我们分析了40名肥胖儿童和40名正常体重儿童的血清FFA、胰岛素、鸢尾素和白色脂肪组织（WAT）转录组。功能验证包括双荧光素酶报告基因检测、原代脂肪细胞模型以及用lncRNA特异性shRNA处理的高脂饮食（HFD）小鼠（每组n = 10）。通过RNA免疫沉淀和蛋白质印迹验证分子相互作用。
与对照组相比，肥胖儿童的FFA水平和HOMA-IR高出2.1倍（P < 0.01），但血清鸢尾素水平低38%，鸢尾素与体脂百分比呈负相关（r = -0.67，P = 0.003）。lncRNA RP11-34D15.2在肥胖WAT中下调了4.3倍，与鸢尾素表达呈正相关（r = 0.603，P = 0.018）。机制研究表明，lncRNA直接结合miR-223（RIP-seq富集倍数 = 5.2，P = 0.004），减轻miR-223介导的对PGC-1α的抑制。在脂肪细胞中过表达lncRNA可使PGC-1α增加2.8倍、鸢尾素增加1.9倍，上调线粒体基因（CPT-1：3.1倍；UCP-1：2.4倍，P < 0.01），并使细胞外FFA降低44%。在HFD小鼠中，lncRNA敲低加剧了葡萄糖不耐受（AUC增加29%，P = 0.007），而补充鸢尾素可恢复胰岛素敏感性（P = 0.013）。
lncRNA RP11-34D15.2作为竞争性内源RNA（ceRNA），通过结合miR-223来激活PGC-1α/鸢尾素介导的线粒体β氧化和FFA清除，为儿童肥胖症确定了治疗靶点。
