Insulin resistance (IR) is the pathophysiological basis of obesity-related metabolic diseases. PVT1 (Plasmacytoma Variant Translocation-1) has been confirmed to be involved in the occurrence and progression of diabetic nephropathy, but its role and mechanism in IR remain unclear. Our study found that:1)The expression of PVT1 was increased in high-fat diet-induced obese IR mice; 2) Specific overexpression of PVT1 by tissue fixed point injection of adenovirus in epididymal adipose tissue promoted IR in obese DIO mice, increased heterotopic lipid deposition, and damaged liver function; 3) Systemic knockdown of PVT1 by tail vein injection of PVT1 shRNA lentivirus effectively improved the IR status of db/db obesity model mice, reduced lipid deposition, reduced liver weight and alleviated liver function injury; 4) PVT1 activated the transcriptional activity of the transcription factor FoxO1 (Forkhead box protein O1), and regulated its downstream target genes such as PEPCK, G6Pase, Gck and Glut4; 5) Knockdown of PVT1 inhibited IRS-PI3K-Akt insulin signaling pathway by activating the phosphorylation of Akt, thus regulated FoxO1 trans-localization; 6) Biotin-RNA Pull-down assay followed by mass spectrometry detection and combined with the CLIP-seq data of RBP-RNA binding in starBaseV3 database showed that PVT1 combines with PTBP1 (Polypyrimidine tract-binding protein-1), proving that PTBP1 was necessary in the process of PVT1 regulating FoxO1 to improve IR, and exploring its specific molecular regulatory mechanism. To sum up, we hope to elucidate the specific molecular mechanism of the regulation of transcription factor FoxO1 by PVT1 combined with PTBP1, so as to provide a new target for the prevention and treatment of IR.


X. Lin: None. W. Gui: None. H. Li: None.


National Natural Science Foundation of China

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