Magnesum Isoglycyrrhizinate augments lipid catabolism via immune-neuro modulation of catecholamine pathways

Glycyrrhetinic acid (GA) and its derivative, magnesium isoglycyrrhizinate, exhibit promising anti-obesity effects through mechanisms that are not fully understood. Here, we showed that GA mitigated white adipose tissue remodeling and diet-induced obesity by enhancing lipid catabolism. GA indirectly promoted adipocyte lipolysis and thermogenesis by modulating catecholamine pathways, facilitated by increased intra-fat sympathetic innervation and reduced protein expression of monoamine oxidase A (MAOA), which degrades norepinephrine. In suit visualization of MAOA identified adipose tissue macrophages (ATMs) as key mediators of intra-fat catecholamine degradation. RNA sequencing of sorted ATMs revealed that GA reduced pro-inflammatory shifts and altered macrophage polarity, preventing activation of the Toll-like receptor 4 (TLR4) signaling pathway, as supported by molecular docking analysis and binding assays. Moreover, the anti-obesity effects of GA were absent in TLR4-deletive mice, which exhibited decreased MAOA protein levels and sensitivity to FUNDC1-mediated mitophagy in ATMs. These findings suggest that GA targets macrophage-sympathetic neuron crosstalk, offering a promising therapeutic approach for obesity by preserving NE availability and promoting lipid catabolism.