Long non-coding RNA Meg3 deficiency impairs glucose homeostasis and insulin signaling by inducing cellular senescence of hepatic endothelium in obesity
Xiao Cheng,
Mohamed Sham Shihabudeen Haider Ali,
Matthew Moran,
Martonio Ponte Viana,
Sarah L. Schlichte,
Matthew C. Zimmerman,
Oleh Khalimonchuk,
Mark W. Feinberg,
Xinghui Sun
Affiliations
Xiao Cheng
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA
Mohamed Sham Shihabudeen Haider Ali
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA
Matthew Moran
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA
Martonio Ponte Viana
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA
Sarah L. Schlichte
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
Matthew C. Zimmerman
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA; Nebraska Redox Biology Center, University of Nebraska - Lincoln, USA
Oleh Khalimonchuk
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA; Nebraska Redox Biology Center, University of Nebraska - Lincoln, USA; Nebraska Center for Integrated Biomolecular Communication, University of Nebraska - Lincoln, USA
Mark W. Feinberg
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Xinghui Sun
Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE, 68588, USA; Nebraska Center for Integrated Biomolecular Communication, University of Nebraska - Lincoln, USA; Nebraska Center for the Prevention of Obesity Diseases Through Dietary Molecules, University of Nebraska - Lincoln, USA; Corresponding author. Department of Biochemistry, Beadle N158, University of Nebraska – Lincoln, 1901 Vine Street, Lincoln, NE, 68588-0665, USA.
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.
