DJ1 ablation enhances CMA activity to exacerbate BAT whitening in humanized mice

Humans predominantly live under thermoneutral conditions, leading to brown adipose tissue (BAT) whitening, a reduction in mitochondrial content and thermogenesis. Here, the adaptations to thermal stress of BAT are examined using quantitative proteomics, finding that Parkinson's disease (PD) pathways are sensitive to ambient temperature. Ablation of DJ-1, a PD gene, exaggerates BAT whitening, resulting in impaired insulin sensitivity and energy expenditure at thermoneutrality. We further identify that the activity of chaperon-mediated autophagy (CMA) contributes to the deletion of DJ-1-induced metabolic phenotypes. Importantly, DJ-1 interacts with HSC70 and subsequently decreases the activity of CMA, enhances the stability of thermogenic proteins. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A counteracts the phenotypes induced by DJ-1 ablation. Additionally, while 4-PBA, an agonist of DJ-1, upregulates mitochondrial oxygen consumption; compound 23, an antagonist of DJ-1, exerts the opposite effects. Collectively, these data address a cell-autonomous route to regulate BAT whitening at thermoneutrality. Overall design: Brown adipose tissues(BAT) from BAT-specific DJ-1 knockout (BDJ1KO) mice and flox mice which were housed at room temperature or 29°C for 8 weeks extracted for RNA sequencing. The sequencing was conducted using Illumina BGIseq500 platform (BGI, China). The transcriptomics data processing was addressed as previous article described. The clean reads were mapped to the reference genome (mm10) using STAR (2.7.10a). Quantification of gene expression was calculated using RSEM (v1.2.28). Subsequently, differential expression analysis between groups was conducted using the DESeq2(1.3.40) with adjust P value < 0.05 and |FC|>1.5. GO enrichment analysis and KEGG pathway analysis was performed by clusterProfiler (4.2.2) with different expression genes.