Anti-Adipogenic Effects of N-Methylatalaphylline in 3T3-L1 Cells Through Modulation of Metabolic and Mitogenic Signaling Pathways

Abstract

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation.