Holt, Marie Kragelund Bachmann; (2017) In vitro and in vivo properties of GLP-1 producing neurons: The brain actions of a gut hormone. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin and neuropeptide primarily known for its role in glucose homeostasis. GLP-1 also has potent anti-obesogenic potential, and is known to inhibit food intake, food reward, and diet-induced obesity. In addition, brain GLP-1 increases heart rate and mediates effects of acute stress. Within the brain, GLP-1 is produced by preproglucagon (PPG) neurons in the caudal brainstem. Although the potential role of GLP-1 has been studied through pharmacological activation of brain GLP-1 receptors, little is known about the cellular properties and physiological role(s) of PPG neurons. In this thesis, a complementary array of in vitro and in vivo techniques was used to study the physiological roles of PPG neurons. In vitro Ca2+ imaging revealed that PPG neuron activity is modulated by a range of compounds relaying signals of energy balance, satiety, and visceral illness. In vivo, I selectively manipulated PPG neurons in mice using chemogenetic tools. Activation of PPG neurons dramatically reduced feeding, supporting a role for brain-derived GLP-1 in appetite control. Although selective inactivation of PPG neurons had no effect on ad libitum feeding, large meal- or stress-induced reductions in food intake were abolished when PPG neurons were silenced. In freely-behaving mice, systemic GLP-1 receptor activation had no effect on arterial blood pressure, but increased heart rate via stimulation of the sympathetic nervous system. Although permanent ablation of PPG neurons had no effect on heart rate and blood pressure, selective activation of PPG neurons using chemogenetic tools increased heart rate. These results provide the first evidence of the physiological role played by the GLP-1 producing neurons in the caudal brainstem. Activity of these neurons is modulated by diverse neural and humoral signals. They are critically important in the prevention of overeating as well as stress-induced hypophagia and may contribute to central nervous mechanisms of cardiovascular control.

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