Abstract 13836: Long Noncoding Rna Meg3 Protects Against Hepatic Endothelial Senescence in Obesity by Regulating Mitochondrial Function

Abstract

Introduction: Long noncoding RNAs (lncRNAs) contribute to the pathogenesis of obesity, a risk factor for cardiovascular disease. The underlying mechanisms are not completely understood, in part, due to that the functions of the majority of them remain unknown in many processes such as mitochondrial homeostasis and cellular senescence. Here, we set out to test the hypothesis that lncRNAs play key roles in obesity by regulating mitochondrial function and cellular senescence in the endothelium. Methods and Results: In this study, transcriptome analysis revealed that lncRNA maternally expressed gene 3 (Meg3) is one of the top induced lncRNAs in the endothelium from adipose tissue in diet-induced obese mice. Meg3 knockdown potentiated obesity-induced insulin resistance revealed by intraperitoneal glucose and insulin tolerance tests and an increase in fasting plasma insulin levels (1.67-fold increase; p<0.05); diminished insulin signaling revealed by 43% reduction (p=0.038) in Akt phosphorylation on serine 473 in liver and, to a lesser extent, in skeletal muscle (32%; p<0.05), but not in visceral fat; and increased hepatic endothelial senescence in obese mice (e.g., 2.74- and 3.40-fold increase in p21 and p16 expression, respectively; p<0.001). Endothelial cell-specific p53 knockout partially attenuated Meg3 knockdown-induced cellular senescence and completely restored hepatic insulin signaling in obese mice. Meg3 knockdown inhibited mitochondrial bioenergetics, increased mitochondrial superoxide production, and caused fragmentation of mitochondrial network; also impaired autophagy, induced a type 1 interferon response, and triggered cellular senescence in HUVECs. Finally, the expression of Meg3 is induced in fatty livers of obese patients and strongly correlates with the cellular senescence marker p16 (r=0.50; p=0.0007). Conclusions: Deficiency of lncRNA Meg3 contributes to mitochondrial dysfunction, hepatic endothelial senescence, and accelerated obesity-induced insulin resistance. Meg3 induction is important in limiting obesity-induced endothelial senescence and insulin resistance, suggesting that manipulation of Meg3 expression may represent a novel approach to manage obesity-associated cardiometabolic disease.