Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophys...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00693/full |
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| author | Liqing Zang Liqing Zang Yasuhito Shimada Yasuhito Shimada Yasuhito Shimada Hiroko Nakayama Hiroko Nakayama Wenbiao Chen Ayaka Okamoto Hiroyuki Koide Naoto Oku Takehisa Dewa Masayuki Shiota Norihiro Nishimura Norihiro Nishimura |
| author_facet | Liqing Zang Liqing Zang Yasuhito Shimada Yasuhito Shimada Yasuhito Shimada Hiroko Nakayama Hiroko Nakayama Wenbiao Chen Ayaka Okamoto Hiroyuki Koide Naoto Oku Takehisa Dewa Masayuki Shiota Norihiro Nishimura Norihiro Nishimura |
| author_sort | Liqing Zang |
| collection | DOAJ |
| description | Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophysiology and reveal potential roles of genetic predisposition. We have previously developed an obesity-induced diabetic zebrafish model that shares common pathological pathways with humans and may be used to identify putative pharmacological targets of diabetes. Additionally, we have previously identified several candidate genes with altered expression in T2DM zebrafish. Here, we performed a small-scale zebrafish screening for these genes and discovered a new therapeutic target, centromere protein X (CENPX), which was further validated in a T2DM mouse model. In zebrafish, cenpx knockdown by morpholino or knockout by CRISPR/Cas9 system ameliorated overfeeding-induced hyperglycemia and upregulated insulin level. In T2DM mice, small-interfering RNA-mediated Cenpx knockdown decreased hyperglycemia and upregulated insulin synthesis in the pancreas. Gene expression analysis revealed insulin, mechanistic target of rapamycin, leptin, and insulin-like growth factor 1 pathway activation following Cenpx silencing in pancreas tissues. Thus, CENPX inhibition exerted antidiabetic effects via increased insulin expression and related pathways. Therefore, T2DM zebrafish may serve as a powerful tool in the discovery of new therapeutic gene targets. |
| first_indexed | 2024-12-13T07:37:35Z |
| format | Article |
| id | doaj.art-a6d9febec8aa4a38b51628dd248b7115 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-13T07:37:35Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-a6d9febec8aa4a38b51628dd248b71152022-12-21T23:55:03ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-07-011010.3389/fgene.2019.00693460897Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes MellitusLiqing Zang0Liqing Zang1Yasuhito Shimada2Yasuhito Shimada3Yasuhito Shimada4Hiroko Nakayama5Hiroko Nakayama6Wenbiao Chen7Ayaka Okamoto8Hiroyuki Koide9Naoto Oku10Takehisa Dewa11Masayuki Shiota12Norihiro Nishimura13Norihiro Nishimura14Graduate School of Regional Innovation Studies, Mie University, Tsu, JapanMie University Zebrafish Drug Screening Center, Tsu, JapanMie University Zebrafish Drug Screening Center, Tsu, JapanDepartment of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, JapanDepartment of Bioinformatics, University Advanced Science Research Promotion Centre, Tsu, Mie, JapanGraduate School of Regional Innovation Studies, Mie University, Tsu, JapanMie University Zebrafish Drug Screening Center, Tsu, JapanDepartment of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United StatesDepartment of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, JapanDepartment of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, JapanDepartment of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, JapanDepartment of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, JapanDepartment of Research Support Platform, Graduate School of Medicine, Osaka City University, Osaka, JapanGraduate School of Regional Innovation Studies, Mie University, Tsu, JapanMie University Zebrafish Drug Screening Center, Tsu, JapanType 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophysiology and reveal potential roles of genetic predisposition. We have previously developed an obesity-induced diabetic zebrafish model that shares common pathological pathways with humans and may be used to identify putative pharmacological targets of diabetes. Additionally, we have previously identified several candidate genes with altered expression in T2DM zebrafish. Here, we performed a small-scale zebrafish screening for these genes and discovered a new therapeutic target, centromere protein X (CENPX), which was further validated in a T2DM mouse model. In zebrafish, cenpx knockdown by morpholino or knockout by CRISPR/Cas9 system ameliorated overfeeding-induced hyperglycemia and upregulated insulin level. In T2DM mice, small-interfering RNA-mediated Cenpx knockdown decreased hyperglycemia and upregulated insulin synthesis in the pancreas. Gene expression analysis revealed insulin, mechanistic target of rapamycin, leptin, and insulin-like growth factor 1 pathway activation following Cenpx silencing in pancreas tissues. Thus, CENPX inhibition exerted antidiabetic effects via increased insulin expression and related pathways. Therefore, T2DM zebrafish may serve as a powerful tool in the discovery of new therapeutic gene targets.https://www.frontiersin.org/article/10.3389/fgene.2019.00693/fullcentromere protein Xtype 2 diabetes mellitusinsulinzebrafish modelCRISPR/Cas9gene silencing |
| spellingShingle | Liqing Zang Liqing Zang Yasuhito Shimada Yasuhito Shimada Yasuhito Shimada Hiroko Nakayama Hiroko Nakayama Wenbiao Chen Ayaka Okamoto Hiroyuki Koide Naoto Oku Takehisa Dewa Masayuki Shiota Norihiro Nishimura Norihiro Nishimura Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus Frontiers in Genetics centromere protein X type 2 diabetes mellitus insulin zebrafish model CRISPR/Cas9 gene silencing |
| title | Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus |
| title_full | Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus |
| title_fullStr | Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus |
| title_full_unstemmed | Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus |
| title_short | Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus |
| title_sort | therapeutic silencing of centromere protein x ameliorates hyperglycemia in zebrafish and mouse models of type 2 diabetes mellitus |
| topic | centromere protein X type 2 diabetes mellitus insulin zebrafish model CRISPR/Cas9 gene silencing |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00693/full |
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