JMJD8 regulates adipocyte hypertrophy through the interaction with Perilipin 2

Adipocyte hypertrophy significantly contributes to insulin resistance and metabolic dysfunction. Our previous research established JMJD8 as a mediator of insulin resistance, noting its role in promoting adipocyte hypertrophy within an autonomous adipocyte context. Nevertheless, the precise mechanisms underlying this phenomenon remained elusive. In this study, we employed a proteomics approach to identify Perilipin 2 (PLIN2), a lipid-associated protein, as a binding partner of JMJD8. Our investigations unveiled a robust interaction between JMJD8 and PLIN2, demonstrating its pivotal role in driving adipocyte hypertrophy and promoting insulin resistance. Furthermore, we show that JMJD8 suppresses fasting-induced lipophagy and curtails energy production, which involves inhibition of PLIN2 phosphorylation. These findings underscore the critical roles played by JMJD8 and PLIN2 in governing lipid droplet homeostasis, while also shedding light on a potential regulatory mechanism governing fat store mobilization during energy deprivation.