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 4

Chronic activation of Gs signaling in K cells improves glucose tolerance in obese K-GsD mice.

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Chronic activation of Gs signaling in K cells improves glucose tolerance...
(A) Body weight gain of 12-week-old K-GsD and control littermates maintained on a HFD and DCZ drinking water for 12 weeks. (B) Fat and lean mass after 11 weeks of HFD feeding. (C) Cumulative food intake of single-housed mice maintained on a HFD for 11 weeks. (D–H) Blood glucose (D) and plasma levels of GIP (E), insulin (F), and GLP1 (G) in nonfasted mice consuming DCZ in the drinking water. Measurements were made 14 days after the initiation of HFD feeding. (H and I) OGTT (1 g/kg) (H) and ITT (1.5 U/kg, i.p.) (I) results after 8–9 weeks of HFD feeding carried out with K-GsD and control mice consuming DCZ in the drinking water. AOC values are shown to the right in each panel. (J–M) Blood glucose (J) and plasma levels of GIP (K), insulin (L), and GLP1 (M) immediately before (time 0) and after 5 and 30 minutes of oral administration of glucose (1 g/kg) in mice consuming DCZ in the drinking water and a HFD for 10 weeks. (N–Q) Intraperitoneal GTT (1 g/kg) (N), blood glucose levels (O), and plasma levels of GIP (P) immediately before (time 0) and after an i.p. glucose bolus (1 g/kg) in mice consuming DCZ in the drinking water and a HFD for 11 weeks. All experiments were performed with male mice after a 6-hour fast (the fasting period was only 4 hours for the ITT studies) (A, B, and H–P). In C–G mice had free access to food. Data are shown as the mean ± SEM (n = 7–9 mice/group). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Tukey’s post hoc analysis (D–G, J–M, and O–P) or 2-tailed, unpaired Student’s t test (A–C, H, I, and N).