Background: Sirt3 is a NAD-dependent deacetylase that regulates lipid metabolism in mice and is related to longevity through modification of epigenome. Sirt3-deficient knockout (KO) mice fed a high-fat diet have been shown to develop obesity and metabolic syndrome-like phenotype. However, the precise mechanism by which they cause glucose intolerance has not been known. To reveal the regulatory mechanism of glucose metabolism through Sirt3, the metabolic parameters in the Sirt3-KO mice were examined.

Objective and Methods: The histone acetylation levels in various organs of the Sirt3-KO mice were examined by immunostaining of acetylated histone H3 (H3Ac) and H4 (H4Ac). Blood glucose levels in the Sirt3-KO mice after glucose loading were examined, associated with blood glucagon-like peptide-1 (GLP-1) levels and dipeptidyl peptidase-4 (DPP-4) activity. Gene expressions which were associated with the expressions and functions of GLP-1 and DPP-4 were quantified by qPCR.

Results: The Sirt3-KO mice were subjected to an oral glucose tolerance test (OGTT), together with an intraperitoneal glucose tolerance test (ipGTT). OGTT revealed an increase in the blood glucose levels in the KO mice, although ipGTT did not show the increase after the glucose loading. The blood GLP-1 and insulin levels decreased, and the DPP-4 activity increased significantly in the KO mice. qPCR analysis revealed a predominance of Sirt3 expression in the intestinal tract in the wild type mice. The immunostaining of H3Ac and H4Ac showed enhanced intensity in the small intestine and colon, and in the vascular endothelial cells in the KO mice.

Conclusion: These results suggest that Sirt3 deficiency impairs the incretin effect by a suppression of the blood GLP-1 levels and causes glucose intolerance. Enhanced acetylation of histone H3 and H4 in the KO mice might relate to the increase in the DPP-4 activity, which lead to the decrease in the GLP-1 levels.


A. Uto: None. K. Miyashita: Research Support; Self; Johnson & Johnson, Merck & Co., Inc., Novo Nordisk Inc.

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