| First Author | Seo SH | Year | 2022 |
| Journal | Clin Transl Med | Volume | 12 |
| Issue | 4 | Pages | e742 |
| PubMed ID | 35384342 | Mgi Jnum | J:334538 |
| Mgi Id | MGI:7435086 | Doi | 10.1002/ctm2.742 |
| Citation | Seo SH, et al. (2022) Inhibition of CXXC5 function reverses obesity-related metabolic diseases. Clin Transl Med 12(4):e742 |
| abstractText | BACKGROUND: Metabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/beta-catenin pathway is a major pathway in adipose tissue remodelling, pancreatic beta-cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5-type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/beta-catenin pathway that functions via Dishevelled (Dvl) binding. METHODS: Expression level of CXXC5 was characterised in clinical samples and diabetes-induced mice model. Diabetes-induced mice model was established by using high-fat diet (HFD). HFD-fed mice treated with KY19334, a small molecule inhibiting CXXC5-Dvl protein-protein interaction (PPI), was used to assess the role of CXXC5 in metabolic diseases. RESULTS: Here, we show that CXXC5 is overexpressed with suppression of Wnt/beta-catenin signalling in visceral adipose tissues of patients with obesity-related diabetes. Meanwhile, Cxxc5(-/-) mice fed an HFD exhibited resistance to metabolic dysregulation. KY19334 restores the lowered Wnt/beta-catenin signalling and reverses metabolic abnormalities as observed in HFD-fed Cxxc5(-/-) mice. Administration of KY19334 on HFD-fed mice had a long-lasting glucose-controlling effect through remodelling of adipocytes and regeneration of pancreatic beta-cells. CONCLUSION: Overall, the inhibition of CXXC5 function by small molecule-mediated interference of Dvl binding is a potential therapeutic strategy for the treatment of obesity-related diabetes. |
