Synergistic potential of Berberine and Wogonin improved adipose inflammation and insulin resistance associated with obesity through HIF-α axis.

backgroundObesity-induced adipose hypoxia activates the hypoxia-inducible factor alpha (HIF-α) axis, where HIF-1α and HIF-2α exhibit functional antagonism: HIF-1α exacerbates insulin resistance (IR) and inflammation, whereas HIF-2α counteracts these effects. This dichotomy suggests dual targeting (inhibiting HIF-1α/activating HIF-2α) could synergistically ameliorate obesity-associated IR. Coptidis Rhizoma and Scutellariae Radix, a classic traditional Chinese medicine (TCM) pair for damp-heat obesity-demonstrate efficacy, but their synergistic components and mechanistic basis remain unclear. Therefore, this study aims to identify active ingredients through the dual targeting strategy and subsequently validate their therapeutic efficacy.

methodsBased on the dual-targeting strategy, potential active ingredients were identified using a specifically designed dual-luciferase reporter system that simultaneously inhibits HIF-1α and activates HIF-2α. The optimal synergistic ratio was determined by applying the Loewe model. In vitro anti-inflammatory efficacy was evaluated in macrophages stimulated with palmitic acid or lipopolysaccharide. In vivo effects were assessed in a high-fat diet-induced obese mouse. Insulin sensitivity was determined by measuring fasting blood glucose levels and performing oral glucose tolerance test and insulin tolerance tests. Tissues were analysed for lipid metabolism and inflammatory markers via immunohistochemistry, quantitative real-time PCR, and enzyme-linked immunosorbent assay.

resultsBerberine (BBR) and wogonin (WOG) were identified from herb pair to inhibit HIF-1α and activate HIF-2α in an optimal synergistic ratio of 3:1. At this ratio, the combination significantly ameliorated the secretion of pro-inflammatory cytokines in vitro. Consistent with the in vitro findings, co-administration of BBR and WOG (3:1) showed lipid-lowering effects comparable to metformin and effectively improved insulin sensitivity in obese mice. Additionally, improved lipid metabolism-related parameters including plasma total cholesterol and free fatty acids, thereby mitigating hepatic lipid accumulation.

conclusionsThe synergistic constituents of Coptidis Rhizoma-Scutellariae Radix, namely BBR and WOG, synergistically alleviate IR associated with obesity by inhibiting HIF-1α and activating HIF-2α, respectively. This study elucidates the mechanistic basis of herbal combination therapy for metabolic disorders and provides a foundation for developing novel synergistic therapeutics against obesity-related IR.