Int J Obes (Lond). 2026 Jul 4. doi: 10.1038/s41366-026-02153-9. Online ahead of print.
ABSTRACT
BACKGROUND: Obesity remains a global health challenge, with limited therapeutic options. Berberine (BBR) shows promise as an anti-obesity agent. However, its clinical application is hampered by modest efficacy and poor bioavailability.
OBJECTIVE: This study investigated the anti-obesity effects and underlying mechanisms of B12, a novel BBR derivative with enhanced solubility and bioavailability.
METHODS: Mice with obesity induced by a high-fat-diet were employed to evaluate B12's effect on weight loss. Energy expenditure was assessed using metabolic cages. Adipose tissue morphology was examined through histological analysis. In vitro studies were conducted using 3T3-L1 preadipocytes and immortalized brown adipocytes. Gene and protein expression were analyzed using RT-qPCR, western blotting, and immunohistochemistry. Cell cycle progression was evaluated by flow cytometry.
RESULTS: B12 demonstrated anti-obesity efficacy superior to BBR, manifesting through dual mechanisms. It enhanced energy expenditure by increasing brown adipocyte numbers and UCP1 expression through SIRT1 upregulation and AMPK phosphorylation. Furthermore, B12 markedly reduced the mass of white adipose tissue in mice with HFD-induced obesity and inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 preadipocytes. This effect was achieved through intervention at multiple stages: early-stage downregulation of CyclinD1 and C/EBPβ, followed by reduced expression and heterodimerization of RXRα and PPARγ during middle and late stages of differentiation, collectively preventing matural adipocyte formation.
CONCLUSIONS: Our findings establish B12 as a promising anti-obesity agent, offering significantly enhanced efficacy over its parent compound BBR. This natural product-derived therapeutic candidate, with its improved pharmacological properties and dual mechanism of action, represents a significant advance in phytomedicine-based approaches to obesity treatment.
PMID:42401759 | DOI:10.1038/s41366-026-02153-9