Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway
Abstract β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acute- and late-phase insulin secret...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2016-02-01
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| Series: | Molecular Medicine |
| Online Access: | http://link.springer.com/article/10.2119/molmed.2015.00155 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Ziwei Lin Yu Zhao Lige Song Kaida Mu Mingliang Zhang Hongxia Liu Xiaowen Li Jian Zhao Chen Wang Weiping Jia |
| spellingShingle |
Ziwei Lin Yu Zhao Lige Song Kaida Mu Mingliang Zhang Hongxia Liu Xiaowen Li Jian Zhao Chen Wang Weiping Jia Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway Molecular Medicine |
| author_facet |
Ziwei Lin Yu Zhao Lige Song Kaida Mu Mingliang Zhang Hongxia Liu Xiaowen Li Jian Zhao Chen Wang Weiping Jia |
| author_sort |
Ziwei Lin |
| title |
Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway |
| title_short |
Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway |
| title_full |
Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway |
| title_fullStr |
Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway |
| title_full_unstemmed |
Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway |
| title_sort |
deletion of β-arrestin2 in mice limited pancreatic β-cell expansion under metabolic stress through activation of the jnk pathway |
| publisher |
BMC |
| series |
Molecular Medicine |
| issn |
1076-1551 1528-3658 |
| publishDate |
2016-02-01 |
| description |
Abstract β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass in βarr2-deficient (βarr2−/−) mice in vivo and explored the underlying mechanisms involved. βarr2−/− mice with exclusively luciferase overexpression in β-cells were generated and fed a high-fat diet (HFD). β-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that β-cell mass was reduced dramatically in βarr2−/− mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU- and Ki67-positive cells reduced in islets from βarr2−/− mice. Exposure of βarr2−/− islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of βarr2 amplified β-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected β-cells from glucose- and FFA-induced cell death through JNK-activation inhibition. In conclusion, βarr2 plays roles in regulation of pancreatic β-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for βarr2 in the development of type 2 diabetes. |
| url |
http://link.springer.com/article/10.2119/molmed.2015.00155 |
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doaj-f998c90e03004cabb754d77d69c660d32020-11-25T00:39:34ZengBMCMolecular Medicine1076-15511528-36582016-02-01221748410.2119/molmed.2015.00155Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK PathwayZiwei Lin0Yu Zhao1Lige Song2Kaida Mu3Mingliang Zhang4Hongxia Liu5Xiaowen Li6Jian Zhao7Chen Wang8Weiping Jia9Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalInstitute of Biochemistry and Cell Biology, Laboratory of Molecular Cell Biology, Chinese Academy of Sciences, Institutes for Biological SciencesShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalAbstract β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass in βarr2-deficient (βarr2−/−) mice in vivo and explored the underlying mechanisms involved. βarr2−/− mice with exclusively luciferase overexpression in β-cells were generated and fed a high-fat diet (HFD). β-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that β-cell mass was reduced dramatically in βarr2−/− mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU- and Ki67-positive cells reduced in islets from βarr2−/− mice. Exposure of βarr2−/− islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of βarr2 amplified β-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected β-cells from glucose- and FFA-induced cell death through JNK-activation inhibition. In conclusion, βarr2 plays roles in regulation of pancreatic β-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for βarr2 in the development of type 2 diabetes.http://link.springer.com/article/10.2119/molmed.2015.00155 |