Ginsenoside Rg1 restores energy homeostasis in glucolipid metabolic disorders by modulating hypothalamic neuroinflammation

Ethnopharmacological relevance: Ginsenoside Rg1 is a major dammarane-type triterpenoid saponin derived from Panax species, including Panax notoginseng, a traditional Chinese medicinal herb. Traditionally, Panax notoginseng and related medicinal Materials have been used to promote blood circulation, stop bleeding, reduce swelling, relieve pain, and enhance vitality. Modern pharmacological studies have demonstrated that Rg1 exhibits a broad range of biological activities, including anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory effects. It has therefore emerged as a promising natural bioactive compound with significant therapeutic potential.

Background: Glucolipid metabolic disorders (GLMD) are chronic conditions characterized by imbalances in glucose and lipid metabolism that severely affect human health. Ginsenoside Rg1, a major active component of ginseng and Panax notoginseng, has shown potential in alleviating neuroinflammation and regulating glucose and lipid metabolism. However, its role in improving metabolic disorders via modulation of neuroinflammation remains poorly understood.

Objective: This study aims to investigate how ginsenoside Rg1 ameliorates GLMD and to elucidate the mechanisms underlying hypothalamic dysfunction in metabolic dysregulation.

Materials and methods: Male Sprague-Dawley rats fed a high-fructose and high-fat diet (HFHFD) were administered ginsenoside Rg1 orally for 6 weeks. Therapeutic effects were evaluated using biochemical assays and histopathological analyses. Relevant targets and pathways were identified using transcriptomic analysis. Inflammatory protein expression was analyzed using Western blotting (WB) and RT-qPCR. In vitro, neuroinflammation was induced in BV2 microglial cells using palmitic acid (PA), and the NF-κB Inhibitor Bay 11-7085 was used to assess protein and cytokine expression.

Results: HFHFD induced significant metabolic disturbances. Ginsenoside Rg1 reduced body weight and adiposity and improved serum lipid profiles. It also alleviated pathological changes in hepatic and adipose tissues. Transcriptomic analysis identified 694 differentially expressed genes associated with hydrogen peroxide metabolism, oxygen transport, and the NF-κB signaling pathway. Rg1 treatment was associated with reduced hypothalamic pro-inflammatory mediators, decreased NF-κB activation, and altered microglial polarization markers. In vitro, direct Rg1 treatment attenuated PA-induced inflammatory activation in BV2 microglial cells, accompanied by decreased IBA1 and iNOS expression and partial restoration of Arg-1 levels.

Conclusion: Ginsenoside Rg1 ameliorates glucolipid metabolic disorders by inhibiting NF-κB signaling, reducing inflammation, and modulating microglial polarization. These findings highlight its therapeutic potential in the treatment of metabolic diseases. In conclusion, Rg1 ameliorates HFHFD-induced glucolipid metabolic disorders and is associated with reduced hypothalamic NF-κB activation and microglial inflammatory markers. Further brain pharmacokinetic studies are needed to determine whether oral Rg1 directly acts on hypothalamic microglia. And brain-specific studies are needed to clarify the causal role of hypothalamic inflammation in Rg1-mediated metabolic improvement.