Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model
Abstract Background The hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involve...
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Diabetology & Metabolic Syndrome |
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| Online Access: | https://doi.org/10.1186/s13098-022-00919-5 |
| _version_ | 1817983931904950272 |
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| author | Edina Pandur István Szabó Edina Hormay Ramóna Pap Attila Almási Katalin Sipos Viktória Farkas Zoltán Karádi |
| author_facet | Edina Pandur István Szabó Edina Hormay Ramóna Pap Attila Almási Katalin Sipos Viktória Farkas Zoltán Karádi |
| author_sort | Edina Pandur |
| collection | DOAJ |
| description | Abstract Background The hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involved in the development of hypothalamic inflammation, which may be one of the underlying causes of a diabetic condition. Moreover, iron may play a role in the pathogenesis of diabetes via the regulation of hepcidin, the iron regulatory hormone synthesis. MicroRNAs (miRNAs) are short non-coding molecules working as key regulators of gene expression, usually by inhibiting translation. Hypothalamic miRNAs are supposed to have a role in the control of energy balance by acting as regulators of hypothalamic glucose metabolism via influencing translation. Methods Using a miRNA array, we analysed the expression of diabetes, inflammation, and iron metabolism related miRNAs in the hypothalamus of a streptozotocin-induced rat type 1 diabetes model. Determination of the effect of miRNAs altered by STZ treatment on the target genes was carried out at protein level. Results We found 18 miRNAs with altered expression levels in the hypothalamus of the STZ-treated animals, which act as the regulators of mRNAs involved in glucose metabolism, pro-inflammatory cytokine synthesis, and iron homeostasis suggesting a link between these processes in diabetes. The alterations in the expression level of these miRNAs could modify hypothalamic glucose sensing, tolerance, uptake, and phosphorylation by affecting the stability of hexokinase-2, insulin receptor, leptin receptor, glucokinase, GLUT4, insulin-like growth factor receptor 1, and phosphoenolpyruvate carboxykinase mRNA molecules. Additional miRNAs were found to be altered resulting in the elevation of FKN protein. The miRNA, mRNA, and protein analyses of the diabetic hypothalamus revealed that the iron import, export, and iron storage were all influenced by miRNAs suggesting the disturbance of hypothalamic iron homeostasis. Conclusion It can be supposed that glucose metabolism, inflammation, and iron homeostasis of the hypothalamus are linked via the altered expression of common miRNAs as well as the increased expression of FKN, which contribute to the imbalance of energy homeostasis, the synthesis of pro-inflammatory cytokines, and the iron accumulation of the hypothalamus. The results raise the possibility that FKN could be a potential target of new therapies targeting both inflammation and iron disturbances in diabetic conditions. Graphical Abstract |
| first_indexed | 2024-04-13T23:39:17Z |
| format | Article |
| id | doaj.art-c571d2dc23d448d3a1e13b2df8e5233b |
| institution | Directory Open Access Journal |
| issn | 1758-5996 |
| language | English |
| last_indexed | 2024-04-13T23:39:17Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj.art-c571d2dc23d448d3a1e13b2df8e5233b2022-12-22T02:24:36ZengBMCDiabetology & Metabolic Syndrome1758-59962022-10-0114111410.1186/s13098-022-00919-5Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes modelEdina Pandur0István Szabó1Edina Hormay2Ramóna Pap3Attila Almási4Katalin Sipos5Viktória Farkas6Zoltán Karádi7Department of Pharmaceutical Biology, Faculty of Pharmacy, University of PécsInstitute of Physiology, Medical School, University of PécsInstitute of Physiology, Medical School, University of PécsDepartment of Pharmaceutical Biology, Faculty of Pharmacy, University of PécsInstitute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of PécsDepartment of Pharmaceutical Biology, Faculty of Pharmacy, University of PécsDepartment of Pharmaceutical Biology, Faculty of Pharmacy, University of PécsInstitute of Physiology, Medical School, University of PécsAbstract Background The hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involved in the development of hypothalamic inflammation, which may be one of the underlying causes of a diabetic condition. Moreover, iron may play a role in the pathogenesis of diabetes via the regulation of hepcidin, the iron regulatory hormone synthesis. MicroRNAs (miRNAs) are short non-coding molecules working as key regulators of gene expression, usually by inhibiting translation. Hypothalamic miRNAs are supposed to have a role in the control of energy balance by acting as regulators of hypothalamic glucose metabolism via influencing translation. Methods Using a miRNA array, we analysed the expression of diabetes, inflammation, and iron metabolism related miRNAs in the hypothalamus of a streptozotocin-induced rat type 1 diabetes model. Determination of the effect of miRNAs altered by STZ treatment on the target genes was carried out at protein level. Results We found 18 miRNAs with altered expression levels in the hypothalamus of the STZ-treated animals, which act as the regulators of mRNAs involved in glucose metabolism, pro-inflammatory cytokine synthesis, and iron homeostasis suggesting a link between these processes in diabetes. The alterations in the expression level of these miRNAs could modify hypothalamic glucose sensing, tolerance, uptake, and phosphorylation by affecting the stability of hexokinase-2, insulin receptor, leptin receptor, glucokinase, GLUT4, insulin-like growth factor receptor 1, and phosphoenolpyruvate carboxykinase mRNA molecules. Additional miRNAs were found to be altered resulting in the elevation of FKN protein. The miRNA, mRNA, and protein analyses of the diabetic hypothalamus revealed that the iron import, export, and iron storage were all influenced by miRNAs suggesting the disturbance of hypothalamic iron homeostasis. Conclusion It can be supposed that glucose metabolism, inflammation, and iron homeostasis of the hypothalamus are linked via the altered expression of common miRNAs as well as the increased expression of FKN, which contribute to the imbalance of energy homeostasis, the synthesis of pro-inflammatory cytokines, and the iron accumulation of the hypothalamus. The results raise the possibility that FKN could be a potential target of new therapies targeting both inflammation and iron disturbances in diabetic conditions. Graphical Abstracthttps://doi.org/10.1186/s13098-022-00919-5HypothalamusIron metabolismDiabetesFractalkineInflammationmiRNA |
| spellingShingle | Edina Pandur István Szabó Edina Hormay Ramóna Pap Attila Almási Katalin Sipos Viktória Farkas Zoltán Karádi Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model Diabetology & Metabolic Syndrome Hypothalamus Iron metabolism Diabetes Fractalkine Inflammation miRNA |
| title | Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model |
| title_full | Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model |
| title_fullStr | Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model |
| title_full_unstemmed | Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model |
| title_short | Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model |
| title_sort | alterations of the expression levels of glucose inflammation and iron metabolism related mirnas and their target genes in the hypothalamus of stz induced rat diabetes model |
| topic | Hypothalamus Iron metabolism Diabetes Fractalkine Inflammation miRNA |
| url | https://doi.org/10.1186/s13098-022-00919-5 |
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