2. Academic Validation
  3. Glycyrrhetinic acid augments lipid catabolism via immune-neural modulation in adipose tissue

Glycyrrhetinic acid augments lipid catabolism via immune-neural modulation in adipose tissue

  • J Adv Res. 2025 Nov 15:S2090-1232(25)00914-2. doi: 10.1016/j.jare.2025.11.019.
Wenjiao Jiang 1,  Sasa Zhang 2,  Xinyuan Sun 3,  Shun Wang 3,  Jinwei Zhu 2,  Ziao Liu 2,  Wanting Zhang 3,  Huijie Guo 2,  Hanwen Li 2,  Hao Xie 4,  Kun Hao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 201210, China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
  • 3 School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 41248711 DOI: 10.1016/j.jare.2025.11.019
Abstract

Introduction: Glycyrrhetinic acid (GA) and its magnesium salt, magnesium isoglycyrrhizinate, exhibit promising anti-obesity effects through mechanisms that are not fully understood.

Objective: This study aims to investigate whether GA mitigated diet-induced obesity and white adipose tissue remodeling by enhancing lipid catabolism.

Methods: The high-fat diet (HFD)-induced obesity is utilized to investigate GA's lipid-lowering effects. The changes in lipid catabolism are validated in vitro and in vivo through secretion rates of glycerol and free fatty acid (FFA), and immunoblotting of lipases. Mice receive GPCR-activation based sensor rAAV-EF1α-DIO-NE1h to visualize simultaneously the norepinephrine (NE) release in adipose tissue. Whole-mount immunostaining of Monoamine Oxidase A (MAOA) highlights the whole-3D imaging of intra-adipose macrophages location surrounding sympathetic nerve fibers. RNA Sequencing (RNA-Seq) of sorted adipose tissue macrophages (ATMs) was used to study GA's mechanisms in regulating obesity progression. And molecular docking identifies a targeting pattern of GA action, which is assayed by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS).

Results: GA indirectly promoted adipocyte lipolysis and thermogenesis by modulating Catecholamine pathways. This modulation is facilitated by increased sympathetic innervation within adipose tissue and a reduction in the protein expression of MAOA, which degrades NE. In situ visualization of MAOA uncovered ATMs as key mediators of Catecholamine degradation within adipose tissues. RNA-Seq of sorted ATMs identified that GA reduced pro-inflammatory shifts and altered macrophage polarity, thereby 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 abolished in TLR4-deficient mice, likely due to the dysfunction of mitophagy-dependent MAOA degradation in ATMs.

Conclusions: Our findings suggest that GA targets macrophage-sympathetic neuron crosstalk in adipose tissues, offering a promising therapeutic approach for obesity.

Keywords

Glycyrrhetinic acid; Immune-neural interaction; Lipid catabolism; Obesity.

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