Blockade of CXXC5-dishevelled interaction inhibits adipogenic differentiation, obesity, and insulin resistance in mice

Obesity has become a major risk factor for developing metabolic diseases, including insulin resistance, type 2 diabetes, and hypertension. Growing pieces of evidence indicate that the Wnt/β-catenin signaling pathway plays an important role in adipogenesis and obesity. Activation of the Wnt/β-catenin signaling pathway inhibits adipogenesis by suppressing the differentiation of committed preadipocytes into mature adipocytes. CXXC5 is highly induced with suppression of Wnt/β-catenin signaling in early adipogenic differentiation. In addition, silencing CXXC5 in vitro increased β-catenin and decremented the major adipogenic differentiation markers. KY19334, a small molecule that activates the Wnt/β-catenin pathway via inhibition of CXXC5- Dishevelled (Dvl) protein–protein interaction (PPI), suppressed adipogenic differentiation. Administration of KY19334 ameliorated obesity by 26 ± 1.3% and insulin resistance by 23.45 ± 7.09% and reduced adipocyte hypertrophy by 80.87 ± 5.30% in high-fat diet (HFD)-fed mice. In addition, KY19334 accelerated the browning of adipose tissue and promoted hepatic glucose homeostasis in HFD-fed mice. In conclusion, activation of the Wnt/β-catenin signaling by inhibiting the interaction of CXXC5 and Dvl by small molecule-mediated interference is a potential therapeutic approach for treating obesity and insulin resistance.