Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits
Antwi-Boasiako Oteng, … , Frank Reimann, Jürgen Wess
Antwi-Boasiako Oteng, … , Frank Reimann, Jürgen Wess
Published October 22, 2024
Citation Information: J Clin Invest. 2024;134(24):e182325. https://doi.org/10.1172/JCI182325.
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Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits

Abstract

Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 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 1 or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the α-subunit of Gs, selectively in K cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K cell Gs 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-KO mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.

Authors

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

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Figure 1

Selective activation of the GsD designer receptor in K cells stimulates GIP secretion in vivo.

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Selective activation of the GsD designer receptor in K cells stimulates ...
(A) Schematic depicting the generation of mice selectively expressing the GsD DREADD in K cells. (B) Representative immunohistochemical images showing colocalization of GIP and GsD (detected with an anti-HA antibody directed against the HA tag fused to the N-terminus of GsD) in the duodenal epithelium of K-GsD mice but not control littermates. White arrows point to individual K cells expressing GsD. Note that the anti-HA antibody caused marked nonspecific staining (staining seen in both control and K-GsD mice).Scale bar: 50 μm. (C) Body weight of 8-week-old K-GsD mice and control littermates consuming regular chow. (D–G) Treatment of K-GsD mice and control littermates with a single oral dose of DCZ (10 μg/kg). Changes in plasma GIP (D), blood glucose (E), plasma insulin (F), and plasma GLP1 (G) levels were monitored at the indicated time points. All experiments were performed with male mice after a 6-hour fast. Data are shown as the mean ± SEM (n = 5 or 6 mice/group). *P < 0.05, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Tukey’s post hoc analysis.