Abstract
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
Highlights
SIRT2 is unique in that it is the only sirtuin known to exist in both the mitochondria and cytosol [1]
SIRT3 is an important regulator of mitochondrial protein acetylation, and changes in its expression could induce changes in the mitochondrial acetylome
Gastrocnemius acetyl-CoA was significantly increased in high fat (HF) SIRT2 KO relative to chow SIRT2 KO mice (S1E Fig), but liver acetyl-CoA was unchanged by diet or genotype (S1F Fig)
Summary
SIRT2 is unique in that it is the only sirtuin known to exist in both the mitochondria and cytosol [1]. H: Immunoblots for SIRT2 in cytosolic (top) and mitochondrial (bottom) protein fractions extracted from gastrocnemius muscle from 5h-fasted WT and SIRT2 KO mice on either a chow of HF diet.
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