IDOL alleviates the body weight by upregulating UCP-1 in mice.

Background: Given the potential role of brown adipose tissue (BAT) in stimulating energy expenditure, activating BAT can be an effective anti-obesity treatment. Here, we aimed to use adenoviruses to establish the effect of the inducible degrader of the low density lipoprotein receptor (IDOL) in the formation of BAT.

Methods: IDOL or green fluorescent protein was overexpressed by adenovirus and injected into the scapula of C57BL/6J mice and fed with high-fat diet for 12 weeks. We measured the body weight, morphology of lipid droplets, lipid profiles and adipogenesis protein expression levels. BAT was isolated, and RNA sequencing was performed to identify the differentially expressed genes and related signaling pathways. Finally, we conducted western blot to verify the authenticity and reliability of the RNA sequencing results.

Results: Compared with the control group, IDOL overexpression led to a significant reduction in body weight, consistent with the weight of adipose tissues and organs. Further studies show IDOL promotion increased ATGL, perilipin 1 and UCP-1 expression in BAT. However, perilipin 1 protein expression was significantly reduced in the Ad-IDOL group in epididymal white adipose tissue, while there was no significant difference in adiponectin, ATGL and perilipin 1 protein expression in inguinal white adipose tissue. Notably, serum FGF21 and leptin protein expression were negatively related to the adipose tissue decrease after Ad-IDOL administration. RNA sequencing analysis identified 1256 differentially expressed genes that were prominently enriched across nine signalling pathways. Additionally, the protein expression of PGAM2, G6PC1 and phosphorylation-AMPK was significantly increased after overexpression IDOL in BAT, which was consistent with the results of the RNA sequencing analysis.

Conclusions: Our research demonstrated that IDOL overexpression alleviates the body weight by promoting the phosphorylation of AMPK to upregulate the UCP-1 and ATGL exacerbating lipolysis in BAT.