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In the status of obesity, the glucagon-like peptide-1 (GLP-1) level usually declines and results in metabolic syndrome. This study aimed to investigate the intracellular mechanism of GLP-1 synthesis in L cells from the perspective of microRNA (miRNA). In the present study, we found that GLP-1 level was down-regulated in the plasma and ileum tissues of obese mice, while the ileac miR-194 expression was up-regulated. In vitro experiments indicated that miR-194 overexpression down-regulated GLP-1 level, mRNA levels of proglucagon gene ( gcg ) and prohormone convertase 1/3 gene ( pcsk1 ), and the nuclear protein level of beta-catenin (β-catenin). Further investigation confirmed that β-catenin could promote  gcg  transcription through binding to transcription factor 7-like 2 (TCF7L2). miR-194 suppressed  gcg  mRNA level via negatively regulating TCF7L2 expression. What’s more, forkhead box a1 (Foxa1) could bind to the promoter of  pcsk1  and enhanced its transcription. miR-194 suppressed  pcsk1  transcription through targeting  Foxa1 . Besides, the interference of miR-194 reduced palmitate (PA)-induced cell apoptosis and the anti-apoptosis effect of miR-194 inhibitor was abolished by TCF7L2 knockdown. Finally, in HFD-induced obese mice, the silence of miR-194 significantly elevated GLP-1 level and improved the metabolic symptoms caused by GLP-1 deficiency. To sum up, our study found that miR-194 suppressed GLP-1 synthesis in L cells via inhibiting TCF7L2-mediated  gcg  transcription and Foxa1-mediated  pcsk1  transcription. Meanwhile, miR-194 took part in the PA-induced apoptosis of L cells.

MicroRNA-194: a novel regulator of glucagon-like peptide-1 synthesis in intestinal L cells