SIRT1 Safeguards Adipogenic Differentiation by Orchestrating Anti-oxidative Responses and Suppressing Cellular Senescence

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 HO 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.