Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

Nat Commun. 2020 Jan 24;11(1):481. doi: 10.1038/s41467-020-14387-w.

Abstract

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, White / metabolism
  • Adipocytes, White / pathology
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Cellular Senescence* / genetics
  • Cellular Senescence* / physiology
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Insulin Resistance* / genetics
  • Insulin Resistance* / physiology
  • Interleukin-1alpha / metabolism
  • Mice
  • Mice, Transgenic
  • Oxidative Stress
  • Progeria / genetics
  • Progeria / metabolism*
  • Progeria / pathology*
  • Promoter Regions, Genetic
  • Receptor, TIE-2 / genetics
  • Signal Transduction
  • Telomeric Repeat Binding Protein 2 / deficiency
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism

Substances

  • Interleukin-1alpha
  • Telomeric Repeat Binding Protein 2
  • Receptor, TIE-2
  • Tek protein, mouse