Tianhuang Formula and its active ingredient GsRg1 ameliorate central insulin resistance and oxidative stress by enhancing hypothalamic autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Tianhuang Formula (THF) has been shown to regulate glucose and lipid metabolism. Maintaining functional hypothalamic autophagy is crucial for central metabolic homeostasis, as its dysregulation leads to insulin resistance and oxidative stress. Nevertheless, the precise functional role and mechanistic basis of THF in regulating glucose and lipid metabolism through the central nervous system require further elucidation.

AIM: The present study was designed to explore the mechanisms through which THF and its principal component, Ginsenoside Rg1 (GsRg1), alleviate central insulin resistance and oxidative stress.

MATERIALS AND

METHODS

Network pharmacology was used to clarify THF's mechanisms in ameliorating central insulin resistance. The effects of THF and its active compound GsRg1 on hypothalamic insulin signaling, oxidative stress and autophagy were then examined in diet-induced obese (DIO) rats and in GT1-7 neurons and BV2 microglia treated with palmitic acid or an autophagy inhibitor.

RESULTS

THF's potential targets in pathways like PI3K/Akt relevant to neuronal activity and insulin resistance were identified through network pharmacology, highlighting GsRg1 as a key active component. In DIO rats and cellular models, THF and GsRg1 improved central insulin signaling by enhancing IRS expression and activating PI3K/Akt, and reduced hypothalamic oxidative stress via the Nrf2 pathway. Critically, they significantly enhanced hypothalamic autophagy in vivo. In vitro experiments using the autophagy activator Rapamycin and the inhibitor 3-MA showed that this autophagic upregulation underpins the improvements in insulin signaling and reductions in oxidative stress.

CONCLUSION

THF and its key component GsRg1 alleviate central insulin resistance and hypothalamic oxidative stress primarily by upregulating hypothalamic autophagy, thereby regulating insulin signaling. GsRg1 is essential for THF's central metabolic benefits.