G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis
Abstract Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54299-7 |
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| author | Srinivas Pittala Dhanush Haspula Yinghong Cui Won-Mo Yang Young-Bum Kim Roger J. Davis Allison Wing Yaron Rotman Owen P. McGuinness Asuka Inoue Jürgen Wess |
| author_facet | Srinivas Pittala Dhanush Haspula Yinghong Cui Won-Mo Yang Young-Bum Kim Roger J. Davis Allison Wing Yaron Rotman Owen P. McGuinness Asuka Inoue Jürgen Wess |
| author_sort | Srinivas Pittala |
| collection | DOAJ |
| description | Abstract Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling. |
| format | Article |
| id | doaj-art-4dfdfbf6265845d1abd626cbda00bf22 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4dfdfbf6265845d1abd626cbda00bf222025-08-20T02:22:29ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54299-7G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasisSrinivas Pittala0Dhanush Haspula1Yinghong Cui2Won-Mo Yang3Young-Bum Kim4Roger J. Davis5Allison Wing6Yaron Rotman7Owen P. McGuinness8Asuka Inoue9Jürgen Wess10Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIHMolecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIHMolecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIHDivision of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDivision of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical SchoolProgram in Molecular Medicine, University of Massachusetts Chan Medical SchoolLiver & Energy Metabolism Section, Liver Diseases Branch, NIDDK, NIHLiver & Energy Metabolism Section, Liver Diseases Branch, NIDDK, NIHDepartments of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine Basic SciencesGraduate School of Pharmaceutical Sciences, Tohoku UniversityMolecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIHAbstract Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling.https://doi.org/10.1038/s41467-024-54299-7 |
| spellingShingle | Srinivas Pittala Dhanush Haspula Yinghong Cui Won-Mo Yang Young-Bum Kim Roger J. Davis Allison Wing Yaron Rotman Owen P. McGuinness Asuka Inoue Jürgen Wess G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis Nature Communications |
| title | G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| title_full | G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| title_fullStr | G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| title_full_unstemmed | G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| title_short | G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| title_sort | g12 13 mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis |
| url | https://doi.org/10.1038/s41467-024-54299-7 |
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