Activation of G_s signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits

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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