GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression

Abstract Excessive adipocyte differentiation and accumulation contribute to the development of metabolic disorders. Growth differentiation factor 15 (GDF15) plays a crucial role in energy homeostasis and is considered an anti-obesity factor; however, increased serum levels of endogenous GDF15 have been reported in certain individuals with obesity. Here, to understand this complex relationship of GDF15 levels with obesity, we investigated its expression and function during early adipogenesis. Mice fed a short-term high-fat diet exhibited a decreased epididymal white adipose tissue and serum GDF15 expression compared to those fed a normal diet. These results were confirmed in human adipose-derived stem cells that showed decreased GDF15 expression during early adipogenesis differentiation. During early adipogenesis, GDF15 was primarily degraded via the autophagy lysosomal pathway, and GDF15 overexpression in preadipocytes inhibited adipogenesis by suppressing the CCAAT enhancer binding protein alpha (C/EBPa). Furthermore, homologous-pairing protein 2 (HOP2) expression decreased during adipogenesis but increased under overexpressed GDF15 conditions. And When HOP2 was knocked down during GDF15 overexpression, there was no suppression of C/EBPa expression. These findings demonstrate that GDF15 undergoes lysosomal degradation through the autophagy pathway and, via HOP2 mediation, suppresses adipocyte differentiation by inhibiting C/EBPa expression. Further, our results suggest that GDF15 could serve as a potential therapeutic target against metabolic disorders.