Glucose uptake is highly induced during cold exposure or feeding in adipocytes, which is utilized as an important energy source for most cells. However, little is known about whether glucose regulates downstream targets that govern thermogenesis and metabolic homeostasis in adipose tissue. Here, we characterize CREB/ATF bZIP transcription factor CREBZF as a novel glucose sensor and regulates thermogenesis via acetylation in adipocytes. Proteomic analysis using LC-MS/MS identifies Lys126 as an evolutionally conserved residue that is acetylated in a glucose-dependent manner. Ectopic expression of CREBZF mutant, in which Lys126 is substituted by alanine, abolishes glucose-stimulated acetylation and protein stabilization of CREBZF. The effects of glucose on protein stabilization of CREBZF are regulated by reversible acetylation that is mediated by transacetylase CBP/p300 and deacetylase HDAC3. Interestingly, endogenous levels of CREBZF are induced by pharmacological inhibition of HDAC3 RGFP966 in SVF-differentiated primary adipocytes. Adipose specific CREBZF knockout (FKO) mice were cold insensitivity and showed enhanced browning and energy metabolism. In the inguinal white adipose tissue (iWAT) of mice in response to cold exposure or β3-adrenergic receptor agonist, the activity of CREBZF is increased, leading to decreased thermogenic gene expression, energy expenditure, and cold tolerance. These findings 1) characterize glucose as a chemical signal to regulate acetylation and stabilization of CREBZF in adipocytes; 2) reveal that Lys126 may play a key role in mediating glucose’s effects on the stimulation of CREBZF activity and inhibition of white adipose tissue browning; 3) uncover an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.
A. Cui: None. W. Su: None. Y. Xue: None. Z. Liu: None. F. Ma: None. Y. Liu: None. Z. Hu: None. Y. Han: None. G. Cai: None. J. Gao: None. E. Chin: None. A. Xu: None. Y. Li: None.
National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Chinese Academy of Sciences (XDA12030210); Shanghai Science and Technology Commission (19140903300)