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SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence.

Authors
  • Yu, An1, 2
  • Yu, Ruofan2
  • Liu, Haiying2
  • Ge, Chenliang1
  • Dang, Weiwei3
  • 1 Yunnan Key Laboratory for Basic Research On Bone and Joint Diseases &, Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, 650214, Yunnan, China. , (China)
  • 2 Baylor College of Medicine, Huffington Center On Aging, 1 Baylor Plaza, Houston, TX, 77030, USA.
  • 3 Baylor College of Medicine, Huffington Center On Aging, 1 Baylor Plaza, Houston, TX, 77030, USA. [email protected].
Type
Published Article
Journal
GeroScience
Publication Date
Feb 01, 2024
Volume
46
Issue
1
Pages
1107–1127
Identifiers
DOI: 10.1007/s11357-023-00863-w
PMID: 37420111
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Adipose tissue is an important endocrine organ that regulates metabolism, immune response and aging in mammals. Healthy adipocytes promote tissue homeostasis and longevity. SIRT1, a conserved NAD+-dependent deacetylase, negatively regulates adipogenic differentiation by deacetylating and inhibiting PPAR-γ. However, knocking out SIRT1 in mesenchymal stem cells (MSCs) in mice not only causes defects in osteogenesis, but also results in the loss of adipose tissues, suggesting that SIRT1 is also important for adipogenic differentiation.Here, we report that severe impairment of SIRT1 function in MSCs caused significant defects and cellular senescence during adipogenic differentiation. These were observed only when inhibiting SIRT1 during adipogenesis, not when SIRT1 inhibition was imposed before or after adipogenic differentiation. Cells generate high levels of reactive oxygen species (ROS) during adipogenic differentiation. Inhibiting SIRT1 during differentiation resulted in impaired oxidative stress response. Increased oxidative stress with H2O2 or SOD2 knockdown phenocopied SIRT1 inhibition. Consistent with these observations, we found increased p16 levels and senescence associated β-galactosidase activities in the inguinal adipose tissue of MSC-specific SIRT1 knockout mice. Furthermore, previously identified SIRT1 targets involved in oxidative stress response, FOXO3 and SUV39H1 were both required for healthy adipocyte formation during differentiation. Finally, senescent adipocytes produced by SIRT1 inhibition showed decreased Akt phosphorylation in response to insulin, a lack of response to adipocytes browning signals, and increased survival for cancer cells under chemotherapy drug treatments. These findings suggest a novel safeguard function for SIRT1 in regulating MSC adipogenic differentiation, distinct from its roles in suppressing adipogenic differentiation. © 2023. The Author(s), under exclusive licence to American Aging Association.

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