The fasting-activated longevity protein sirtuin 1 (SirT1, ref. 1) promotes gluconeogenesis in part, by increasing transcription of the key gluconeogenic genes pepck1 and g6pase2,3, through deacetylating PGC-1α and FOXO1 (ref. 4). In contrast, signal transducer and activator of transcription 3 (STAT3) inhibits glucose production by suppressing expression of these genes5,6. It is not known whether the inhibition of gluconeogenesis by STAT3 is controlled by metabolic regulation. Here we show that STAT3 phosphorylation and function in the liver were tightly regulated by the nutritional status of an animal, through SirT1-mediated deacetylation of key STAT3 lysine sites. The importance of the SirT1–STAT3 pathway in the regulation of gluconeogenesis was verified in STAT3-deficient mice in which the dynamic regulation of gluconeogenic genes by nutritional status was disrupted. Our results reveal a new nutrient sensing pathway through which SirT1 suppresses the inhibitory effect of STAT3, while activating the stimulatory effect of PGC-1α and FOXO1 on gluconeogenesis, thus ensuring maximal activation of gluconeogenic gene transcription. The connection between acetylation and phosphorylation of STAT3 implies that STAT3 may have an important role in other cellular processes that involve SirT1.
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We thank M. Shanabrough for her technical support and careful revision of this manuscript. Some constructs were obtained from Y. E. Chin, W. Gu, P. Yao, E. Seto and D. Levy. SirT1, PGC-1α adenovirus was a gift from P. P. Puigserver. SirT1 KO MEFs and wild-type MEFs were a gift from L. P. Guarente. Part of this work was supported by an ADA grant to Q. G. (1-08-RA-54) and NIH grants to T. L. H. (DK-08000 and DK-060711), G. I. S. (DK-40936 and DK-076169) and J.L.B. (DK-P30-34989). The preparation of primary hepatocytes was performed in the Liver Center of Yale University School of Medicine. SirT1 ASO and Control ASO were provided by ISIS Pharmaceuticals, Inc.
The authors declare no competing financial interests.
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