Remodelling of the acetylproteome by SIRT3 manipulation fails to affect insulin secretion or beta-cell metabolism in the absence of over nutrition

From Peterson et. al. 2018: SIRT3 is an NAD+-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in b-cells, resulting in wide-spread, SIRT3dependent changes in acetylation of key metabolic enzymes, but with no appreciable changes in glucose- or pyruvate-stimulated insulin secretion, or in metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress conditions. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high- fat/high-sucrose (HFHS) diets. Only when chronically fed a HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism.