Seol Hwa Seo¹ Eunhwan Kim¹ Soung-Hoon Lee² Yong-ho Lee³ Dai Hoon Han⁴ Hyesun Go⁵ Je Kyung Seong⁵ Kang-Yell Choi^1,2

¹Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea ²CK Regeon Inc., Seoul, Republic of Korea ³Department of Internal Medicine, Yonsei University, Seoul, Republic of Korea ⁴Department of surgery, Yonsei University College of Medicine, Seoul, Republic of Korea ⁵Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic ofKorea

Correspondence Kang-Yell Choi

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/β-catenin pathway is a major pathway in adipose tissue remodelling, pancreatic β-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/β-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/β-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/β-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 β-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.