image: ZNF638 in brown adipose tissue (BAT) exacerbates type 1 diabetes (T1D) by suppressing retinol-binding protein 4 (RBP4), thereby disrupting all-trans retinoic acid (ATRA)-mediated protection of pancreatic β-cells
Credit: ©Science China Press
T1D is an autoimmune disorder characterized by immune-mediated destruction of insulin-producing pancreatic β-cells, resulting in absolute insulin deficiency. Insulin, often termed the metabolic key, facilitates glucose uptake into cells for energy production. Its absence disrupts systemic glucose homeostasis, leading to life-threatening complications including diabetic ketoacidosis, nephropathy, cardiovascular disease, and retinol-pathway. While genetic susceptibility and environmental triggers are known to initiate β-cell autoimmunity, the molecular mechanisms underlying progressive β-cell loss remain incompletely understood. BAT, traditionally recognized for its thermogenic function in energy expenditure through uncoupling protein 1 (UCP1), has emerged as an endocrine organ secreting adipokines that regulate systemic metabolism. However, its role in T1D pathogenesis has remained elusive.
The researchers employed a multi-disciplinary approach combining molecular biology and in vivo modeling to dissect BAT-islet communication. Using streptozotocin (STZ)-induced T1D mouse models, they demonstrated that ZNF638 expression in BAT is significantly upregulated under hyperglycemic conditions. Mechanistic investigations revealed a ZNF638-RBP4-retinol-ATRA regulatory cascade: Firstly, hyperglycemia activates carbohydrate response element-binding protein β (ChREBPβ), a glucose-sensing transcription factor that induces ZNF638 transcription. Secondly, ZNF638 forms a heterodimeric complex with peroxisome proliferator-activated receptor γ (PPARγ) to bind to the PPAR response element (PPRE) on the RBP4 promoter for transcriptional repression. Thirdly, suppressed RBP4 levels impaired retinol shuttling from BAT to pancreatic islets, leading to reduced islet levels of ATRA, the bioactive metabolite of retinol, to maintain β-cell viability via activation of retinoic acid receptor (RAR)-mediated anti-apoptotic gene expression.
The team generated BAT-specific ZNF638 overexpression (BOE) via local adenoviral injection and adipose-specific knockout (FKO) mice using Cre-LoxP recombination technology. BOE mice exhibited impaired glucose tolerance, reduced serum retinol level, and increased β-cell apoptosis compared to wild-type controls. Conversely, FKO mice showed restored RBP4 expression, normalized ATRA levels, and preserved β-cell mass, with blood glucose levels reduced compared to STZ-induced T1D mice. Of note, RBP4 levels and retinol levels were decreased in the serum of T1D patients compared to healthy controls.
“This work establishes an unappreciated endocrine link between adipose tissue and pancreatic islets, opening new avenues for understanding T1D progression”. Explained by the corresponding author, Xinran Ma from East China Normal University. “ZNF638 acts as a master regulator of BAT-islet crosstalk. Targeting the ZNF638-RBP4-retinol-ATRA axis represents a promising strategy to halt T1D progression.”
This work advances diabetic research by identifying ZNF638 as the key BAT-specific transcriptional regulator for T1D pathogenesis, establishing the RBP4-retinol-ATRA pathway as a critical endocrine link between adipose tissue and pancreatic islets, and proposing targeting the ZNF638-RBP4-retinol-ATRA axis against T1D.
Journal
Science Bulletin