The mitochondrial
enzyme SIRT3 is an
NAD+-dependent deacetylase important in cell metabolism, and a decline in its
protein expression or activity has been linked with
insulin resistance in
obesity, ageing and
type 2 diabetes. While studies in
SIRT3 knockout mice have dramatically improved our understanding of the function of
SIRT3, the impact of increasing
SIRT3 levels remains under-examined. In this study we investigated the effects of liver-specific
SIRT3 overexpression in mice on mitochondrial function and metabolic profile in both isolated hepatocytes and in vivo. Primary hepatocytes overexpressing
SIRT3 displayed increased oxygen consumption and a reduction in
triglyceride accumulation. In mice with hepatic
SIRT3 overexpression, increased fasting β-hydroxybutyrate levels were observed, coupled with an increase in oxygen consumption in isolated mitochondria and increased substrate utilization in liver homogenates. However, metabolic profiling of mice exposed to either chow or high-fat diet revealed no effect of hepatic
SIRT3 overexpression on
glucose tolerance, body composition or tissue
triglyceride accumulation. These findings suggest limited whole-body benefit of increasing hepatic
SIRT3 during the development of diet-induced
insulin resistance.