GDF15 Mediates the Anti-Obesity Effects of Ursolic Acid via Coordinated Regulation of Lipid Metabolism

Obesity is a metabolic syndrome characterized by the excessive accumulation of adipose tissue. Ursolic acid (UA) modulates diverse metabolic processes, including the amelioration of metabolic syndrome and attenuation of hepatic steatosis. However, the specific effects and underlying mechanisms by which UA ameliorates high-fat diet (HFD)-induced obesity and associated metabolic disorders remain to be elucidated. In this study, we investigated the ameliorative effects of UA on obesity using an HFD-induced obese mouse model and a sodium oleate-induced HepG2 cell model. Our results demonstrated that UA supplementation significantly reduced HFD-induced weight gain and visceral fat mass, lowered serum and hepatic total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels while increasing high-density lipoprotein cholesterol (HDL-C) levels, attenuated hepatic steatosis with a marked reduction in hepatic TG content, and suppressed inflammation with decreased serum and hepatic interleukin-18 (IL-18) and interleukin-1β (IL-1β) levels. Correspondingly, in HepG2 cells, UA mitigated sodium oleate-induced TG and TC accumulation, decreased intracellular ROS, and lowered IL-18 and IL-1β secretion. Additionally, UA upregulated the lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) at both protein and mRNA levels, downregulated the lipogenic factors sterol regulatory element-binding protein 1c (SREBP1c) and stearoyl-CoA desaturase 1 (SCD-1), and suppressed absent in melanoma 2 (AIM2) and apoptosis-associated speck-like protein containing a CARD (ASC) expression. Notably, we identified growth differentiation factor 15 (GDF15) as a critical upstream mediator of UA’s multifaceted effects. UA robustly upregulated GDF15 expression both in vivo and in vitro, and siRNA-mediated knockdown of GDF15 completely abolished UA’s beneficial actions, including its regulation of lipolysis/lipogenesis, inhibition of the AIM2 inflammasome, reduction in oxidative stress, and attenuation of lipid accumulation. In summary, our findings reveal that UA ameliorates obesity-related metabolic disorders and inflammation by modulating GDF15 expression, which in turn coordinately regulates lipid catabolism/anabolism pathways and AIM2 inflammasome activation. These results establish the UA-GDF15 axis as a promising therapeutic target for the treatment of obesity and its metabolic complications.