Triazole-Based Inhibitors of the Wnt/β-Catenin Signaling Pathway Improve Glucose and Lipid Metabolisms in Diet-Induced Obese Mice

Wnt/beta-catenin signaling pathway is implicated in the etiology and progression of metabolic disorders. Although lines of genetic evidence suggest that blockage of this pathway yields favorable outcomes in treating such ailments, few inhibitors have been used to validate the promising genetic findings. Here, we synthesized and characterized a novel class of triazole-based Wnt/beta-catenin signaling inhibitors and assessed their effects on energy metabolism. One of the top inhibitors, compound 3a, promoted Axin stabilization, which led to the proteasome degradation of beta-catenin and subsequent inhibition of the Wnt/beta-catenin signaling in cells. Treatment of hepatocytes and high fat diet-fed mice with compound 3a resulted in significantly decreased hepatic lipid accumulation. Moreover, compound 3a improved glucose tolerance of high fat diet-fed mice without noticeable toxicity, while downregulating the genes involved in the glucose and fatty acid anabolisms. The new inhibitors are expected to be further developed for the treatment of metabolic disorders.