The sirtuin family of deacylase enzymes have been linked with the regulation of numerous metabolic processes. SIRT5 is a mitochondrial sirtuin that has recently been shown to remove a variety of newly-identified post-translational modifications (PTMs) including succinyl, malonyl, and glutaryl modifications. The physiological processes that alter these PTMs and the consequences of manipulating levels of SIRT5 on metabolic outcomes remains relatively unexplored. We sought to investigate the metabolic profile of mice with transgenic overexpression of SIRT5, under normal chow conditions and in response to a high fructose diet, where we predicted the elevated levels of malonyl-CoA would result in alterations in malonylation.

10 -14 week old SIRT5 transgenic mice (SIRT5TG) and wildtype (WT) littermates were placed on either a chow (CH) or high-fructose (FF) diet for 13 weeks. Transgenic mice overexpress SIRT5 protein ~10-fold in liver as assessed by western blot, however the level of SIRT5 was not affected by diet. Consistent with our prediction, fructose-feeding significantly elevated global malonylation of proteins in the liver, but this was not markedly different in SIRT5TG mice, when assessed by western blot with a pan malonyl-lysine antibody. Fructose-fed mice showed significantly higher body fat percentage by echoMRI (23.4±2.5 FF vs. 14.0±1.6 CH p<0.0001), however adiposity was not modulated by SIRT5. Fructose-feeding significantly elevated liver triglyceride 1.6-fold (p<0.05), but to an equal extent in both WT and SIRT5TG mice. Glucose tolerance (dosed per g lean mass) was impaired in response to the FF diet (AUC 416±52 FF vs. 243±48 CH, p=0.015) and appeared to be further impaired (p=0.03) in the SIRT5TG mice (AUC 542±82 FF vs. 401±49 CH).

These results suggest that whole-body overexpression of SIRT5 may have effects on whole body glucose tolerance that warrant further investigation, despite having no effect on body composition, liver triglyceride or weight gain.