Obesity is a worldwide leading health concern and is associated with serious complications including type 2 diabetes and cardiovascular disease. Understanding how nutrients are sensed in the body to regulate energy and glucose homeostasis may identify new approaches to the prevention and treatment of metabolic disease.

The functional pathways of a lipid sensing receptor, G protein-coupled receptor 119 (GPR119), and its relationship with GLP-1 in energy homeostasis, were investigated in using a mouse model. A GPR119 agonist significantly improved oral glucose tolerance, and evidence suggested that this effect was regulated by GLP-1 receptor (GLP-1R) activation. Additionally, the expression of the GPR119 receptor was detected in mice nodose ganglia, where the neuronal cell bodies of vagal afferent neurons are located. The sensitivity of the vagus nerve to nutrients and gut hormones has been suggested to be influenced by nutritional status. Therefore, the expression of GPR119 in the nodose ganglia under fasting and ad libitum fed conditions was compared, but no difference was observed. Activating GPR119 on primary mice nodose ganglia cells increased intracellular Ca2+ mobilisation. Oral administration of GPR119 synthetic or endogenous ligands to mice increased neuronal activation, as determined by c-Fos expression, in the dorsal vagal complex of brainstem and the dopaminergic A13 cells of the hypothalamus. Based on these results, we hypothesized that the activation of GPR119 might influence gastric motility and flavour preference. However, we found no significant effects of GPR119 ligands on these parameters. Further studies are required to confirm the relationships between the vagus nerve and GPR119-mediated physiological changes.

The wider mRNA expression profile of individual mouse nodose ganglia cells and changes that occur with altered nutritional status were investigated using single nucleus RNA sequencing. Cluster analysis identified the same cell clusters in left and right ganglia and in fed and fasted ganglia. The nuclei expressing selective hormone or nutrient receptors were organised into subsets for functional analysis. Fasting resulted in significant changes in gene expression in all populations of cells identified in the nodose ganglia, including changes in genes associated with energy homeostasis.

Together this project has investigated nutrient sensing in the gut brain axis, particularly focusing on the GPR119 and the vagus nerve. The results suggest that GPR119 plays a role in glucose homeostasis, but further work is required to determine the role of the vagus in mediating its biological effects. The results of the RNA sequencing of the nodose ganglia suggest that these neurons are sensitive to nutritional state. Further work is now required to assess whether any of the cell types within the nodose represent useful targets for pharmacotherapies for metabolic disease.