Triterpenoids – future multi-target compounds against obesity and towards restoration of metabolic health

Obesity and its associated diseases represent one of the most urgent public health crises of our time, affecting billions worldwide. Current pharmacological agents, such as GLP-1 and GLP-1/GIP receptor agonists, have demonstrated high clinical efficacy in diabetes and weight management. However, the required lifelong medication is often limited by high economic costs and severe side effects, including gastrointestinal complications. Consequently, the search for complementary therapies is invaluable. This review highlights the potential of natural triterpenoids in obesity management by shifting the focus towards long-term metabolic restoration. Triterpenoids can serve as multi-target agents that address key pathways, such as AMPK and Akt/mTOR, thereby positively regulating autophagy processes and improving metabolic imbalances. Celastrol, for example, acts as a leptin sensitizer, restoring satiety signaling; ursolic acid drives body recomposition by enhancing energy expenditure; and ginsenosides modulate multiple processes, including browning, adipogenesis, lipogenesis, and satiety signaling. Furthermore, oleanolic acid promotes pathways associated with cellular healthspan by activating telomerase, while betulinic acid suppresses de novo fatty acid synthesis independently of food intake. However, low oral bioavailability remains the major challenge to successfully translating these findings from animal models to clinical applications. Advanced strategies, such as sustainable bioproduction via genetically modified microorganisms, engineered probiotics, or nanotechnology-based delivery systems, offer promising opportunities to overcome these pharmacokinetic and safety limitations. Addressing these barriers is essential to translate triterpenoids into therapeutic agents for human metabolic health and healthy aging.