Berberine combined with stachyose protects against obesity by modulating gut microbiota and increasing leptin sensitivity.

Leptin resistance is a hallmark of obesity. Recent evidence shows that gut microbiota is associated with the development and progression of leptin resistance. However, whether intervention targeting gut microbiota can improve leptin sensitivity remains to be fully established. In the current investigation, we have demonstrated that co-administration of berberine, an isoquinoline alkaloid compound, and stachyose, a prebiotic, could enhance leptin sensitivity and reduce body weight in diet-induced obesity (DIO) mice, via an effect associated with gut microbiota modulation. Notably, the combination of berberine and stachyose significantly increased the abundance of Blautia producta, altered host purine metabolism, and elevated serum and hypothalamic levels of a purine metabolite, inosine. Furthermore, direct supplementation with inosine further ameliorated inflammation and endoplasmic reticulum stress in the hypothalamus and improved leptin sensitivity in obese mice. These findings suggest that berberine combined with stachyose represents a novel leptin sensitizer for obesity, acting through the modulation of gut microbiota and subsequently alteration in host purine metabolism, particularly with the involvement of inosine.