Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease

Nat Metab. 2020 Dec;2(12):1482-1497. doi: 10.1038/s42255-020-00320-4. Epub 2020 Dec 14.

Abstract

White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra+ cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb+ lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / pathology*
  • Adipocytes, Beige / metabolism
  • Adipocytes, White / metabolism
  • Aging / pathology*
  • Animals
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cell Proliferation
  • Diet, High-Fat
  • Female
  • Humans
  • Insulin Resistance / genetics
  • Intra-Abdominal Fat
  • Male
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Stem Cells / pathology*
  • Subcutaneous Fat / metabolism
  • Subcutaneous Fat / pathology
  • Telomerase / genetics
  • Telomerase / metabolism
  • Telomere Homeostasis*

Substances

  • Receptor, Platelet-Derived Growth Factor alpha
  • Telomerase
  • Tert protein, mouse