311-OR: CREBZF as a Novel Target of Glucose Sensing Signaling in the Control of Adaptive Thermogenesis in the Adipose Tissue

Although glucose is generally considered to be required for generating heat during cold-induced nonshivering thermogenesis in the adipose tissue, whether it engages nutrient sensing pathways in the adipose tissue to negatively regulate thermogenesis and impairs metabolic homeostasis remains largely unknown. Here we report CREB/ATF bZIP transcription factor CREBZF as a key target of adipocyte glucose sensing signaling that exerts a negative effect on the adaptive thermogenesis in the adipose tissue. We found that CREBZF was significantly induced in inguinal white adipose tissue (iWAT) in response to cold exposure or β3AR agonist treatment, which was associated with an induced expression of glucose transporter genes such as GLUT1 and GLUT4. To elucidate the function of CREBZF, we generated adipose-specific CREBZF knockout (CREBZF FKO) mice. Compared with WT mice, CREBZF FKO mice exhibited enhanced browning of iWAT and thermogenic capacity in response to acute and chronic cold exposure. Moreover, CREBZF FKO mice were less cold sensitive. In the adipocyte, CREBZF was induced by glucose treatment, which was associated with increased acetylation of CREBZF. Interestingly, the protein stability of CREBZF was dynamically regulated by reversible acetylation mediated by transacetylase CREB-binding protein (CBP) and deacetylase HDAC. Deletion of CBP ameliorated glucose-induced CREBZF. Proteomic analysis was performed to identify potential acetylation sites of CREBZF. Furthermore, CREBZF associated with PGC-1α and inhibited its transcription activity. Together, we propose that in addition to its role as a fuel source to promote thermogenesis, glucose may act as a chemical signal to stimulate CREBZF activity and cause impaired browning and thermogenesis in the adipose tissue. This study uncovers an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.