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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Research Article Endocrinology

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 2

Stimulation of K cell Gs signaling results in improved glucose tolerance in lean K-GsD mice.

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Stimulation of K cell Gs signaling results in improved glucose tolerance...
(A and B) OGTTs. (A) K-GsD mice and control littermates received glucose only (2 g/kg). (B) Both groups of mice were treated with glucose plus oral DCZ (10 μg/kg). (C and D) ITTs. (C) K-GsD and control mice received insulin only (0.75 U/kg, i.p.). (D) Both groups of mice received i.p. insulin plus DCZ (10 μg/kg). Area-of-the-curve (AOC) values are given as quantitative measures of the experimental data shown in A–D. (E–G) Cotreatment of K-GsD and control mice with oral glucose plus DCZ (10 μg/kg). Plasma GIP (E), plasma insulin (F), and plasma GLP1 (G) levels were measured at the indicated time points. (H) OGTT after oral coadministration of glucose and DCZ 48 hours after treatment with a GIP receptor antibody (GIPRAb). All experiments were carried out with male mice after a 6-hour fast (the fasting period was only 4 hours for the ITT studies). Data are shown the mean ± SEM (n = 7 or 8 mice/group). **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Tukey’s post hoc analysis (E–G) or 2-tailed, unpaired Student’s t test (A–D and H).