The preventive effects of tetrahydroberberine on male obese mice and its uptake by adipocytes are associated with the D2R-PI3K axis and OCT2.

Obesity arises from a chronic imbalance between energy intake and consumption that culminates in pathological adipose tissue expansion, ectopic lipid deposition, and persistent low-grade inflammation. Tetrahydroberberine, the principal reductive metabolite of berberine, exhibits potent lipid-lowering and fat-targeting activities. However, the causal link between adipocyte uptake of tetrahydroberberine and its preventive treatment effects against obesity remains undefined. This study investigated the uptake of tetrahydroberberine by MDI-induced hypertrophic 3T3-L1 adipocytes and in high-fat diet-induced obese male C57BL/6J mice, as well as its efficacy in the prophylactic treatment of obesity. The results demonstrated that tetrahydroberberine reduced body weight, epididymal fat mass, and perirenal fat mass, while ameliorating pathological changes in the adipose tissue of male obese mice. Moreover, tetrahydroberberine ameliorated lipid accumulation and inflammatory responses in both adipocytes and adipose tissues. Mechanistically, these effects were associated with inhibition of the dopamine receptor D2 (D2R)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway, which in turn suppressed leptin-mediated expressions of sterol regulatory element binding protein type 1c (SREBP-1C) and peroxisome proliferator-activated receptor γ (PPAR-γ). The findings also revealed that tetrahydroberberine primarily enters adipocytes via organic cation transporter 2 (OCT2). Notably, inhibition of the D2R/PI3K axis by tetrahydroberberine elevated OCT2 expression, thereby enhancing its uptake by adipocytes. Collectively, these findings demonstrate that the uptake of THB by hypertrophic adipocytes exerts an inhibitory effect on the development of obesity by regulating the D2R-PI3K axis and OCT2.