Indirubin-3'-oxime, an activator of Wnt/β-catenin signaling, enhances osteogenic commitment of ST2 cells and restores bone loss in high-fat diet-induced obese male mice

Abstract

Obesity is a growing issue of the modern world, and its negative impact on bones in obese male patients has been recently reported. The Wnt/β-catenin pathway has an established role in the regulation of body fat content and bone density. We investigated the effects of indirubin-3'-oxime (I3O), the GSK3β inhibitor that activates Wnt/β-catenin signaling, on trabecular bone in high-fat diet (HFD)-induced obese male mice. I3O reverses the downregulating effect of fatty acid (FA) on Wnt/β-catenin signaling and enhances the osteogenic commitment of the bone marrow-derived stromal cell line ST2. FA induces the adipogenic differentiation of bone marrow stromal cells in vitro. In a male mouse model of HFD-induced obesity, trabecular bone loss was observed in the femora, with a gross increase in abdominal fat; however, the HFD effects were rescued with the activation of Wnt/β-catenin signaling by I3O treatment. I3O administration also reversed the increase in the number of HFD-induced adipocytes in the femur bone marrow in trabecular bone. Overall, our results indicate that I3O could be a potential therapeutic agent for obese male patients through downregulation of abdominal fat and net increment in trabecular bone density.

Keywords: Abdominal fat; Bone loss; GSK3β inhibitor; Indirubin-3′-oxime; Obesity; Wnt/β-catenin.