RBM15 suppresses hepatic insulin sensitivity of offspring of Gestational Diabetes Mellitus Mice via m6A-mediated regulation of CLDN4

Abstract

Background Gestational diabetes Mellitus (GDM)is a common pregnancy-specific disease with high morbidity, which is linked to a high risk of obesity and diabetes in offspring. N6-methyladenosine modification of RNA is emerging as an important epigenetic mechanism that is widely manifested in many diseases. Emerging evidence revealed that m6A is involved in various disease, however, the role of m6A methylation in metabolic syndrome in offspring result from intrauterine hyperglycemia remains unclear. This study aimed to investigate the mechanism of m6A in regulation of hepatic insulin sensitivity. Results In this study, we found that offspring from a GDM mother were more vulnerable to glucose intolerance and insulin resistance. GC-MS revealed significant metabolic changes including saturated fatty acids and unsaturated fatty acids in liver of GDM offspring. We also demonstrated that global mRNA m6A methylation level was significantly increased in the fetal liver of GDM mice, indicating epigenetic change may have a strong relationship with the mechanism of metabolism syndrome. Concordantly, RBM15, the RNA binding methyltransferase, was upregulated in the liver. In vitro, RBM15 suppressed insulin sensitivity and increased insulin resistance through m6A-regulated epigenetic inhabitation of CLDN4. Moreover, MeRIP-sequencing and mRNA-sequencing revealed that differently regulated genes with differential m6A peaks were enriched in metabolic pathways. Conclusion Our study revealed the essential role of RBM15 in insulin resistance and the effect of RBM15-regulated m6A modification in the metabolic syndrome of offspring of GDM mice.

Insulin and Exercise-induced Phosphoproteomics of Human Skeletal Muscle Identify REPS1 as a New Regulator of Muscle Glucose Uptake

“…This included known insulin-(upregulation of RPS6 S236/T241, TBC1D4 S341, TSC2 S939 and downregulation of GYS1 S645) and exercisesignaling proteins (upregulation of STIM1 S257, ACACB S222 and downregulation of PDHA1 S300) as well as new insulin signaling proteins, such as the S741 phosphosite on the RNA-binding protein 15, RBM15, which was downregulated in response to insulin. Interestingly, RBM15 was recently associated with liver insulin resistance through epigenetic m6A regulation 33 . Our comprehensive phosphoproteomic analysis encompassing insulin and exercise stimuli in the same individuals represents a valuable resource for the scientific community (Supplementary table 1A-C).…”