Long non-coding RNA Meg3 deficiency impairs glucose homeostasis and insulin signaling by inducing cellular senescence of hepatic endothelium in obesity

Abstract

Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. However, the mechanisms underlying endothelial senescence in obesity, and how it impacts obesity-induced insulin resistance remain incompletely understood. In this study, transcriptome analysis revealed that the long non-coding RNA (lncRNA) Maternally expressed gene 3 (Meg3) is one of the top differentially expressed lncRNAs in the vascular endothelium in diet-induced obese mice. Meg3 knockdown induces cellular senescence of endothelial cells characterized by increased senescence-associated β–galactosidase activity, increased levels of endogenous superoxide, impaired mitochondrial structure and function, and impaired autophagy. Moreover, Meg3 knockdown causes cellular senescence of hepatic endothelium in diet-induced obese mice. Furthermore, Meg3 expression is elevated in human nonalcoholic fatty livers and nonalcoholic steatohepatitis livers, which positively correlates with the expression of CDKN2A encoding p16, an important hallmark of cellular senescence. Meg3 knockdown potentiates obesity-induced insulin resistance and impairs glucose homeostasis. Insulin signaling is reduced by Meg3 knockdown in the liver and, to a lesser extent, in the skeletal muscle, but not in the visceral fat of obese mice. We found that the attenuation of cellular senescence of hepatic endothelium by ablating p53 expression in vascular endothelium can restore impaired glucose homeostasis and insulin signaling in obesity. In conclusion, our data demonstrate that cellular senescence of hepatic endothelium promotes obesity-induced insulin resistance, which is tightly regulated by the expression of Meg3. Our results suggest that manipulation of Meg3 expression may represent a novel approach to managing obesity-associated hepatic endothelial senescence and insulin resistance.

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

“…Moreover, we found that Meg3 deficiency promoted cellular senescence of the hepatic endothelium with no or minimal effects on cellular senescence of other cell types in the liver in diet-induced obese mice ( Cheng et al, 2021 ). Importantly, Meg3 knockdown impaired systemic glucose homeostasis and insulin signaling in the liver, which can be restored by attenuating the cellular senescence of hepatic endothelium, indicating that cellular senescence of the vascular endothelium impairs glucose homeostasis and insulin signaling in obesity ( Cheng et al, 2021 ). How Meg3 limits cellular senescence of ECs is unclear.…”

“…Meg3 knockdown causes cellular senescence of HUVECs characterized by accelerated telomere length shortening, an increase in the levels of superoxide, an increase in SA-β-gal activity, impaired autophagy, and mitochondrial dysfunction (Lan et al, 2019;Cheng et al, 2021). Moreover, we found that Meg3 deficiency promoted cellular senescence of the hepatic endothelium with no or minimal effects on cellular senescence of other cell types in the liver in diet-induced obese mice (Cheng et al, 2021). Importantly, Meg3 knockdown impaired systemic glucose homeostasis and insulin signaling in the liver, which can be restored by attenuating the cellular senescence of hepatic endothelium, indicating that cellular senescence of the vascular endothelium impairs glucose homeostasis and insulin signaling in obesity FIGURE 4 | The role of maternally expressed gene 3 (Meg3) in regulating endothelial cellular senescence.…”

“…Importantly, Meg3 knockdown impaired systemic glucose homeostasis and insulin signaling in the liver, which can be restored by attenuating the cellular senescence of hepatic endothelium, indicating that cellular senescence of the vascular endothelium impairs glucose homeostasis and insulin signaling in obesity FIGURE 4 | The role of maternally expressed gene 3 (Meg3) in regulating endothelial cellular senescence. (Cheng et al, 2021). How Meg3 limits cellular senescence of ECs is unclear.…”

“…Senescent ECs seem to display a different senescence-associated metabolic shift. Studies revealed that senescent ECs have a decline in glycolysis ( Unterluggauer et al, 2008 ; Kuosmanen et al, 2018 ), or in mitochondria-mediated oxidative phosphorylation ( Kim Y. M. et al, 2018 ; Haemmig et al, 2020 ; Cheng et al, 2021 ). So what could be the energy source for senescent programming and SASP in ECs?…”

“…These effects of Meg3 knockdown are mediated in part by its protein binding partner PTBP3. Meg3 knockdown causes cellular senescence of HUVECs characterized by accelerated telomere length shortening, an increase in the levels of superoxide, an increase in SA-β-gal activity, impaired autophagy, and mitochondrial dysfunction ( Lan et al, 2019 ; Cheng et al, 2021 ). Moreover, we found that Meg3 deficiency promoted cellular senescence of the hepatic endothelium with no or minimal effects on cellular senescence of other cell types in the liver in diet-induced obese mice ( Cheng et al, 2021 ).…”