Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes
ABSTRACT Aims/Introduction Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP g...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | Journal of Diabetes Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/jdi.14142 |
| _version_ | 1797234159054225408 |
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| author | Yusuke Shiozaki‐Takagi Nobuaki Ozaki Yukiyasu Toyoda |
| author_facet | Yusuke Shiozaki‐Takagi Nobuaki Ozaki Yukiyasu Toyoda |
| author_sort | Yusuke Shiozaki‐Takagi |
| collection | DOAJ |
| description | ABSTRACT Aims/Introduction Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes. Materials and Methods Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac‐specific activator, 8‐CPT, and an Epac‐specific inhibitor, ESI‐05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes. Results Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8‐CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI‐05 failed to reverse glucagon‐induced suppression of glycogen storage and partially inhibited glucagon‐induced GK translocation and the mRNA expression of gluconeogenic enzymes. Conclusions Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes. |
| first_indexed | 2024-04-24T16:27:38Z |
| format | Article |
| id | doaj.art-0808263fc07f490bb97dc27e761b4477 |
| institution | Directory Open Access Journal |
| issn | 2040-1116 2040-1124 |
| language | English |
| last_indexed | 2024-04-24T16:27:38Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Investigation |
| spelling | doaj.art-0808263fc07f490bb97dc27e761b44772024-03-30T10:00:09ZengWileyJournal of Diabetes Investigation2040-11162040-11242024-04-0115442943610.1111/jdi.14142Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytesYusuke Shiozaki‐Takagi0Nobuaki Ozaki1Yukiyasu Toyoda2Research Center of Health, Physical Fitness and Sports Nagoya University Nagoya JapanResearch Center of Health, Physical Fitness and Sports Nagoya University Nagoya JapanDepartment of Pathobiochemistry, Faculty of Pharmacy Meijo University Nagoya JapanABSTRACT Aims/Introduction Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes. Materials and Methods Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac‐specific activator, 8‐CPT, and an Epac‐specific inhibitor, ESI‐05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes. Results Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8‐CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI‐05 failed to reverse glucagon‐induced suppression of glycogen storage and partially inhibited glucagon‐induced GK translocation and the mRNA expression of gluconeogenic enzymes. Conclusions Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes.https://doi.org/10.1111/jdi.14142EPACGlucagonGlucogenic action |
| spellingShingle | Yusuke Shiozaki‐Takagi Nobuaki Ozaki Yukiyasu Toyoda Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes Journal of Diabetes Investigation EPAC Glucagon Glucogenic action |
| title | Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes |
| title_full | Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes |
| title_fullStr | Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes |
| title_full_unstemmed | Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes |
| title_short | Epac2 activation mediates glucagon‐induced glucogenesis in primary rat hepatocytes |
| title_sort | epac2 activation mediates glucagon induced glucogenesis in primary rat hepatocytes |
| topic | EPAC Glucagon Glucogenic action |
| url | https://doi.org/10.1111/jdi.14142 |
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