Regulation of Peroxisome Proliferator–Activated Receptor-γ Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis

TLDR

Adipocyte differentiation is essential for metabolic homeostasis and nutrient signaling, and the mTOR pathway mediates this process, yet rapamycin’s inhibitory effect on differentiation remains mechanistically unclear. The authors propose that mTOR and PI3K/Akt pathways act in parallel to regulate PPAR‑γ activation during adipogenesis, integrating nutrient availability and insulin signaling. They found that mTOR kinase activity is essential for 3T3‑L1 differentiation, rapamycin disrupts the C/EBPα‑PPARγ feedback loop by inhibiting PPARγ transactivation, PPARγ activity requires amino‑acid sufficiency, and troglitazone can rescue differentiation, suggesting therapeutic avenues.

Abstract

Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process. Rapamycin specifically disrupted the positive transcriptional feedback loop between CCAAT/enhancer-binding protein-α and peroxisome proliferator–activated receptor-γ (PPAR-γ), two key transcription factors in adipogenesis, by directly targeting the transactivation activity of PPAR-γ. In addition, we demonstrate for the first time that PPAR-γ activity is dependent on amino acid sufficiency, revealing a molecular link between nutrient status and adipogenesis. The results of our further investigation have led us to propose a model in which the mTOR pathway and the phosphatidylinositol 3-kinase/Akt pathway act in parallel to regulate PPAR-γ activation during adipogenesis by mediating nutrient availability and insulin signals, respectively. It is interesting that troglitazone (a thiazolidinedione drug) reversed the inhibitory effects of rapamycin and amino acid deprivation, implicating therapeutic values of thiazolidinedione drugs to counter certain side effects of rapamycin as an immunosuppressant.