Endocrine Abstracts (2019) 65 P193 | DOI: 10.1530/endoabs.65.P193

Modulation of vagal afferent signalling by the amino acid metabolite sensor GPR35

Anna Roberts, Sijing Cheng, Mariana Norton, Omer Mohamed, Simon C Cork, Victoria Salem, Aylin Hanyaloglu & Kevin Murphy

Imperial College, London, UK

High dietary protein intake can suppress appetite, drive weight loss and improve glucose homeostasis. Understanding the mechanisms by which ingested protein is sensed may reveal new therapeutic targets for metabolic disease. G-protein coupled receptor 35 (GPR35) is activated by compounds including Kynurenic acid (Kyna), a product of amino acid metabolism. GPR35 is expressed in the intestines, most highly in the colon, and has recently been identified in the afferent vagus nerve, an important component of the gut–brain axis in the regulation of energy expenditure and glucose homeostasis. Interestingly, only a small number of post-prandial metabolite-recognising receptors have been identified in vagal afferents. GPR35 was the most abundantly expressed. We therefore investigated the effects of GPR35 agonists on vagal signalling. We confirmed GPR35 expression in both left and right nodose ganglia (NG) in mice. However, GPR35 expression was not changed in the NG or colon following a 24 h fast, in contrast to previously reported changes in other appetite-suppressing receptors (e.g. Y2-R). GPR35-like immunostaining was identified in epithelial cells in the mouse duodenum and colon, and in putative nerve axons in submucosal and muscular layers of duodenal and ileum slices. In vitro calcium imaging using cultured murine NG cells demonstrated that the GPR35 agonist Kyna modulates signalling in vagal neurons. Treatment with 15 uM Kyna or the synthetic GPR35 agonist Zaprinast, increased intracellular calcium mobilisation compared to non-GPR35 expressing HEK293 cells. Inositol phosphate-1 accumulation similarly increased post-treatment with Kyna, supporting likely GPR35-activation in a Gq-mediated manner. Further work is required to establish the physiological effects of GPR35 signalling in the vagus to determine whether this system mediates some of the beneficial effects of high protein diets.

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