88-OR: Glucose Regulation of Adipose Tissue Browning by CBP/p300 and HDAC3-Mediated Reversible Acetylation of CREBZF

Glucose uptake is highly induced under cold exposure in adipose tissue, and glucose is required for generating heat during cold-induced nonshivering thermogenesis. However, the regulatory mechanism is largely unknown. Here, we uncovered a glucose sensor, a novel metabolic regulator CREBZF, that mediates the regulatory effects of glucose on browning of adipose tissue. In human white adipose tissue and inguinal white adipose tissue (iWAT) in mice, expression levels of CREBZF were remarkably induced by glucose. Glucose administration induces rectal temperature and thermogenesis in white adipose of control mice. Interestingly, these effects are further potentiated by CREBZF deficiency in adipose tissue. Consistently, during cold exposure, adipose tissue-specific CREBZF knockout mice display enhanced thermogenic gene expression, browning of iWAT and adaptive thermogenesis. Mechanistically, Lys208 acetylation modulated by transacetylase CREB-binding protein (CBP)/p300 mediates the glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Moreover, deacetylase HDAC3 interacts with and removes the acetylation modification of CREBZF. The induced CREBZF by glucose further associates with PGC-1α and represses its transcriptional activity on thermogenic gene expression. Importantly, expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic condition. Our results reveal an unknown mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.