Jiang, Wanqing; (2025) Central GLP-1 System: Physiological Roles and Its Potential as an Anti-obesity Target. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Obesity is a major public health challenge. Brain glucagon-like peptide-1 receptors (GLP-1Rs) suppress feeding upon activation, and GLP-1 receptor agonists (GLP-1RAs) are currently the most effective anti-obesity drugs. GLP-1RAs act primarily on circumventricular organs due to limited brain access. Endogenously, GLP-1 is released in the gut as an incretin and in the brain as an anorexigenic neuropeptide, with brainstem pre-proglucagon (PPG) neurons serving as the primary source of central GLP-1. Recent findings revealed that PPG neurons suppress food intake through mechanisms distinct from GLP-1RAs, underscoring their untapped potential as anti-obesity targets. Brainstem PPG neurons are distributed across two distinct regions: the nucleus tractus solitarius (NTS) and the intermediate reticular nucleus (IRT), with PPG neurons in the IRT remaining largely unexplored. This thesis investigated both populations to provide a more comprehensive understanding of brainstem PPG neurons. Using anterograde and retrograde viral tracing, it was demonstrated that PPGNTS and PPGIRT neurons share overlapping projection patterns but receive distinct synaptic inputs and have minimal direct interactions. Single-nucleus RNA sequencing further revealed these populations to be molecularly distinct. Functional studies showed that near complete ablation of both PPGNTS and PPGIRT neurons significantly increased food intake and body weight, highlighting their necessity in regulating ad libitum feeding. Chronic chemogenetic activation of both populations reduced food intake and body weight in a sustained manner in obese mice. Additionally, combining a PPG neuron-dependent drug (5-HT2C receptor agonist) with a PPG neuron-independent drug (GLP-1RA) produced a greater anorexigenic effect than each drug alone. This thesis provided a comprehensive characterisation of the anatomical and molecular features of brainstem PPG neurons and established, for the first time, their necessity in regulating ad libitum feeding. It highlighted their potential as anti-obesity targets and offered proof of concept for combining PPG neuron activation with GLP-1RAs to enhance anti-obesity outcomes.

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