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

Wnt/β-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/β-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 β-catenin
and subsequent inhibition of the Wnt/β-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.