High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis

Abstract Chronic nutrient excess drives adipose tissue fibrosis and inflammation, key features of metabolic dysfunction that underlie insulin resistance and Type 2 diabetes. However, the molecular mechanisms linking hyperglycemia to pathological adipose tissue remodeling remain less understood. Here, we identify a post-translational mechanism by which high glucose destabilizes PRDM16, a key transcriptional regulator of adipose tissue identity, through O-GlcNAcylation of its E3 ligase adaptor protein, amyloid beta precursor protein binding protein 2 (APPBP2). Glucose-induced O-GlcNAcylation of APPBP2 at S561 promotes its interaction with PRDM16, triggering PRDM16 ubiquitination and proteasomal degradation. Notably, APPBP2S561N is a hypomorphic variant identified in human populations who exhibit improved glucose homeostasis. Knock-in mice harboring APPBP2S561N maintained elevated PRDM16 protein levels independently of mRNA abundance and are protected against diet-induced adipose tissue fibrosis, inflammation, glucose intolerance, and insulin resistance. These metabolic benefits are independent of UCP1-mediated thermogenesis, as metabolic protection of APPBP2S561N persists in the Ucp1 null background. These findings reveal a glucose-responsive O-GlcNAc pathway that couples nutrient excess to adipose tissue dysfunction through post-translational regulation of PRDM16 protein stability.