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 6

Metabolic studies with K-Gs–KO mice maintained on regular chow.

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Metabolic studies with K-Gs–KO mice maintained on regular chow. (A) Sche...
(A) Schematic depicting the generation of K-Gs–KO mice that lack Gαs selectively in enteroendocrine K cells. (B) Transcript levels of Gnas, the gene that encodes Gαs, measured with RNA prepared from duodenal FACS-sorted K cells and non–K cells. (C) Representative images of H&E staining experiments showing that the lack of Gαs in K cells did not affect the overall morphology of the proximal intestine/duodenum. Original magnification, ×40 (top row) and ×60 (bottom row). (D–G) K-Gs–KO mice and control littermates showed similar body weights (D), whole intestine weights (E), and intestinal contents of GIP (F) and GLP1 (G). (H and I) K-Gs–KO mice showed reduced plasma GIP levels (H), but unchanged plasma GLP1 levels (I). (J) Cumulative food intake measured over 5 days in single-housed mice. (K–Q) Metabolic parameters of K-Gs–KO mice and control littermates after refeeding following a 24-hour fast. Body weights (K), blood glucose levels (L), and plasma levels of NEFAs (M), GIP (N), insulin (O), GLP1 (P), and glucagon (Q). All experiments were performed with male mice. In B–I, mice were subjected to a 6-hour fast. Data are shown as the mean ± SEM (n = 7–9 mice/group). *P < 0.05, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Tukey’s post hoc analysis (K–Q) or 2-tailed, unpaired Student’s t test (B and D–J).