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.
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BibTeX
@misc{kajimura2026high,
title = {{High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis}},
author = {Shingo Kajimura and Yong Chen and Li Chen and Yusuke Higuchi and Daisuke Kato and Qiang Wang},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11471586/v1},
url = {https://doi.org/10.21203/rs.3.rs-11471586/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis
AU - Shingo Kajimura
AU - Yong Chen
AU - Li Chen
AU - Yusuke Higuchi
AU - Daisuke Kato
AU - Qiang Wang
PY - 2026
DA - 2026/10/30
PB - Research Square
DO - 10.21203/rs.3.rs-11471586/v1
UR - https://doi.org/10.21203/rs.3.rs-11471586/v1
AB - 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.
SN - 2693-5015
ER -