Inhibition of CXXC5 function reverses obesity‐related metabolic diseases
Abstract 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, panc...
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.742 |
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| author | Seol Hwa Seo Eunhwan Kim Soung‐Hoon Lee Yong‐ho Lee Dai Hoon Han Hyesun Go Je Kyung Seong Kang‐Yell Choi |
| author_facet | Seol Hwa Seo Eunhwan Kim Soung‐Hoon Lee Yong‐ho Lee Dai Hoon Han Hyesun Go Je Kyung Seong Kang‐Yell Choi |
| author_sort | Seol Hwa Seo |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T09:59:02Z |
| format | Article |
| id | doaj.art-cfc2fa4033174e65bb724473a93971a1 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-10T09:59:02Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-cfc2fa4033174e65bb724473a93971a12022-12-22T01:53:23ZengWileyClinical and Translational Medicine2001-13262022-04-01124n/an/a10.1002/ctm2.742Inhibition of CXXC5 function reverses obesity‐related metabolic diseasesSeol Hwa Seo0Eunhwan Kim1Soung‐Hoon Lee2Yong‐ho Lee3Dai Hoon Han4Hyesun Go5Je Kyung Seong6Kang‐Yell Choi7Department of Biotechnology College of Life Science and Biotechnology Yonsei University Seoul Republic of KoreaDepartment of Biotechnology College of Life Science and Biotechnology Yonsei University Seoul Republic of KoreaCK Regeon Inc. Seoul Republic of KoreaDepartment of Internal Medicine Yonsei University Seoul Republic of KoreaDepartment of surgery Yonsei University College of Medicine Seoul Republic of KoreaKorea Mouse Phenotyping Center Seoul National University Seoul Republic of KoreaKorea Mouse Phenotyping Center Seoul National University Seoul Republic of KoreaDepartment of Biotechnology College of Life Science and Biotechnology Yonsei University Seoul Republic of KoreaAbstract 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.https://doi.org/10.1002/ctm2.742adipose tissue remodellingCXXC5metabolic diseasespancreatic β‐cell regenerationWnt/β‐catenin pathway |
| spellingShingle | Seol Hwa Seo Eunhwan Kim Soung‐Hoon Lee Yong‐ho Lee Dai Hoon Han Hyesun Go Je Kyung Seong Kang‐Yell Choi Inhibition of CXXC5 function reverses obesity‐related metabolic diseases Clinical and Translational Medicine adipose tissue remodelling CXXC5 metabolic diseases pancreatic β‐cell regeneration Wnt/β‐catenin pathway |
| title | Inhibition of CXXC5 function reverses obesity‐related metabolic diseases |
| title_full | Inhibition of CXXC5 function reverses obesity‐related metabolic diseases |
| title_fullStr | Inhibition of CXXC5 function reverses obesity‐related metabolic diseases |
| title_full_unstemmed | Inhibition of CXXC5 function reverses obesity‐related metabolic diseases |
| title_short | Inhibition of CXXC5 function reverses obesity‐related metabolic diseases |
| title_sort | inhibition of cxxc5 function reverses obesity related metabolic diseases |
| topic | adipose tissue remodelling CXXC5 metabolic diseases pancreatic β‐cell regeneration Wnt/β‐catenin pathway |
| url | https://doi.org/10.1002/ctm2.742 |
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