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
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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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 7

Reduced plasma GIP levels in K-Gs–KO mice do not affect whole-body glucose homeostasis.

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Reduced plasma GIP levels in K-Gs–KO mice do not affect whole-body gluco...
All studies were carried out with male K-Gs–KO mice and control littermates consuming regular chow. (A–D) Blood glucose levels (A) and plasma levels of GIP (B), insulin (C), and GLP1 (D), immediately before (time 0) and 10 minutes after treatment with an oral glucose bolus (2 g/kg). (E and F) OGTTs (2 g/kg) (E) and ITTs (0.75 U/kg, i.p.) (F) were administered. AOC values are shown to the right in each panel. (G–K) Blood glucose levels (G) and plasma levels of GIP (H), insulin (I), GLP1 (J), and NEFAs (K), immediately before (time 0) and 1 hour after oral gavage with olive oil (10 μL/g). All experiments were performed with male mice after a 6-hour fast (the fasting period was only 4 hours for the ITT studies). Data are shown as the mean ± SEM (n = 7–10 mice/group). *P < 0.05, **P < 0.01, and ****P < 0.000, by 2-way ANOVA followed by Tukey’s post hoc analysis (A–D and G–K) or 2-tailed, unpaired Student’s t test (E and F).