Sirt3 Overexpression In Neurons Enables Beta-Oxidation And Prevents Palmitate-Induced Insulin Resistance

The mitochondrial NAD+-dependent deacetylase Sirtuin3 (SIRT3) controls adaptive responses to metabolic stresses. As a result, SIRT3 knockout mice exhibit mitochondrial dysfunction and are prone to neurodegeneration. High levels of circulating free fatty acids are associated with mitochondrial dysfunction, oxidative stress and insulin resistance (IR), features of metabolic and neurodegenerative diseases. We show that neurons treated with the saturated fatty acid palmitate exhibit reduced SIRT3 expression, mitochondrial dysfunction and IR. We hypothesized that SIRT3 protects neurons from lipid-induced mitochondrial dysfunction and IR as observed in metabolic disorders. To test this, we overexpressed SIRT3 in the murine hypothalamic cell line CLU183 (SIRT3OE) and analyzed its effect on neuronal metabolism under basal and lipotoxic conditions. Under basal condition, SIRT3OE neurons reflected the phenotype of palmitate-treated control cells, characterized by IR, mitochondrial dysfunction, and oxidative stress. Yet under lipotoxic conditions, SIRTOE neurons were partially protected against palmitate-induced IR, mitochondrial dysfunction and oxidative stress. Strikingly SIRT3OE neurons were able to metabolize palmitate indicating that SIRT3 may regulate lipid sensing in neurons.