Cook, Daniel Reece; (2019) The role of the preproglucagon neurons in cardiovascular control, energy homeostasis and glucose homeostasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glucagon-like peptide-1 (GLP-1) is produced in the gut and central nervous system. Microinjection of GLP-1 analogues into specific brain regions causes hypophagia, induces insulin release and tachycardia. GLP-1 is produced within the brain by preproglucagon (PPG) neurons, situated in the caudal brainstem. PPG neurons project to nuclei involved in cardiovascular control, glucose homeostasis, and food intake. I hypothesised that PPG neurons are the endogenous source of GLP-1 in the brain, and their activation should reproduce the effects seen upon injection of exogenous GLP-1 into the brain. I demonstrated that selective chemogenetic activation of PPG neurons increased heart rate, but, their inhibition did not reduce it. These results demonstrate that PPG neurons can modulate heart rate but are not doing so under resting conditions. Similarly, I showed that PPG neuron activation acutely but not chronically decreases food intake. To further understand under which circumstances PPG neurons are activated to control food intake, c-Fos- immunoreactivity (C-Fos-IR) was used to detect neuronal activity in response to stimuli. There were few C-Fos-IR positive PPG neurons with normal feeding, but intake of highly palatable Ensure (Vanilla milkshake) substantially increased the number of C-Fos-IR positive PPG neurons suggesting that they are activated when consuming a high calorific and/or a high-volume meal. This suggests that PPG neurons induce satiety only in response to large or palatable meals. Neither chemogenetic activation nor ablation of the PPG neurons affected glucose tolerance, arguing that PPG neurons do not modulate blood glucose levels. The results presented here provide evidence for the physiological role of PPG neurons in satiety, implicating them as a possible target for weight loss drugs. Additionally, PPG neurons are capable of raising heart rate, however further studies must define under which conditions PPG neurons induce tachycardia. As these results mimic the effects of exogenous GLP-1, it seems likely that PPG neurons induce satiety and tachycardia through the release of GLP-1.

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