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The phosphorylation status of T522 modulates tissue‐specific functions of SIRT 1 in energy metabolism in mice
Author(s) -
Lu Jing,
Xu Qing,
Ji Ming,
Guo Xiumei,
Xu Xiaojiang,
Fargo David C,
Li Xiaoling
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643803
Subject(s) - national park , environmental research , library science , signal transduction , biological sciences , medicine , biology , geography , ecology , biochemistry , computational biology , computer science , environmental planning
Abstract SIRT 1, the most conserved mammalian NAD + ‐dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT 1 is regulated in vivo remain unclear. Here, we report that phosphorylation modification of T522 on SIRT 1 is crucial for tissue‐specific regulation of SIRT 1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho‐T522 level is reduced during adipogenesis. Knocking‐in a constitutive T522 phosphorylation mimic activates the β‐catenin/ GATA 3 pathway, repressing PPAR γ signaling, impairing differentiation of white adipocytes, and ameliorating high‐fat diet‐induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT 1 in response to over‐nutrition. Hepatic SIRT 1 is hyperphosphorylated at T522 upon high‐fat diet feeding. Knocking‐in a SIRT 1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high‐fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT 1 phosphorylation, and energy homeostasis and demonstrate that the phosphorylation of T522 is a critical element in tissue‐specific regulation of SIRT 1 activity in vivo .