Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits

Antwi-Boasiako Oteng; Liu Liu; Yinghong Cui; Oksana Gavrilova; Huiyan Lu; Min Chen; Lee S. Weinstein; Jonathan E. Campbell; Jo E. Lewis; Fiona M. Gribble; Frank Reimann; Jürgen Wess

doi:10.1172/JCI182325

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Oteng, A. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Liu, L. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Cui, Y. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Gavrilova, O. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Lu, H. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Chen, M. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Weinstein, L. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Campbell, J. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Lewis, J. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Gribble, F. in: JCI | PubMed | Google Scholar |

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Reimann, F. in: JCI | PubMed | Google Scholar

¹Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

²Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

³Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁴Signal Transduction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States of America

⁵Duke Molecular Physiology Institute, Duke University, Durham, United States of America

⁶MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom

Find articles by Wess, J. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI182325.
Copyright © 2024, Oteng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 22, 2024 - Version history

Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell G_s. First, we generated a mouse model that allowed us to selectively stimulate K-cell G_s signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of G_s, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell G_s signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell G_s signaling may prove useful for the treatment of diabetes and related metabolic diseases.

Version 1 (October 22, 2024): In-Press Preview

Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits

Antwi-Boasiako Oteng,¹ Liu Liu,¹ Yinghong Cui,¹ Oksana Gavrilova,² Huiyan Lu,³ Min Chen,⁴ Lee S. Weinstein,⁴ Jonathan E. Campbell,⁵ Jo E. Lewis,⁶ Fiona M. Gribble,⁶ Frank Reimann,⁶ and Jürgen Wess¹

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Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits

Antwi-Boasiako Oteng,1 Liu Liu,1 Yinghong Cui,1 Oksana Gavrilova,2 Huiyan Lu,3 Min Chen,4 Lee S. Weinstein,4 Jonathan E. Campbell,5 Jo E. Lewis,6 Fiona M. Gribble,6 Frank Reimann,6 and Jürgen Wess1

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Antwi-Boasiako Oteng,¹ Liu Liu,¹ Yinghong Cui,¹ Oksana Gavrilova,² Huiyan Lu,³ Min Chen,⁴ Lee S. Weinstein,⁴ Jonathan E. Campbell,⁵ Jo E. Lewis,⁶ Fiona M. Gribble,⁶ Frank Reimann,⁶ and Jürgen Wess¹