Central Neural Mechanisms Underlying Weight Loss Driven by GLP-1 Receptor Agonism and Immune Challenge

Abstract

Disruptions in the brain’s control of body weight can lead to obesity or involuntary weight loss. GLP-1R agonists have transformed obesity care, but the brain-mediated mechanisms behind their success remain unclear. Involuntary weight loss is a common problem during inflammatory and infectious conditions for which there is currently no effective treatment. The overall aim of this thesis was to fill knowledge gaps in how GLP-1R agonists and inflammatory agents act on the brain to reduce feeding and promote weight loss, with focus on brainstem-derived mechanisms. Semaglutide is the most efficient mono-agonist in clinical use. The drug activates neurons in the area postrema (AP) and nucleus of the solitary tract (NTS) of the dorsal vagal complex (DVC) and using activity-dependent neuronal targeting, we could chemogenetically reactivate these specific neurons and identified many of these as positive for Adcyap1 mRNA. Reactivation of semaglutide-responsive DVC neurons reproduced key physiological outcomes observed during drug treatment, including effects on food intake, body weight, and fat utilization. Importantly, ablation of AP/NTS Adcyap1⁺ neurons reduced several semaglutide-induced effects on energy balance in lean and obese mice. Furthermore, they promoted fat loss over lean mass, with minimal impact on semaglutide-induced conditioned taste aversion. We also observed that NTS Adcyap1⁺ neurons were engaged by AP Glp1r+ neurons and the ablation of these Adcyap1⁺ neurons attenuated the brain-wide activation pattern induced by the drug. Semaglutide treatment reduced activation of AgRP neurons in the arcuate nucleus through pathways involving NTS Adcyap1⁺ neurons and experimentally increasing AgRP neuron activity diminished the weight-lowering effects of semaglutide in obese mice. Optogenetic activation of projections from NTS Adcyap1⁺ neurons to the arcuate and dorsomedial hypothalamus reduced feeding under highly motivated and hedonic conditions and induced a catabolic state but did not cause aversion. We further examined a role for AP/NTS Gfral+ neurons in mediating inflammation-induced weight loss. Viral double-stranded RNA sensed via toll-like receptor 3 (TLR3) was associated with increased circulating growth differentiation factor 15 and engagement of AP/NTS Gfral+ neurons, in parallel with reductions in food intake and body weight. Brain-wide activation mapping showed that these TLR3-responsive AP/NTS neurons engage brain regions involved in feeding control and energy balance. Together, this work positions AP/NTS Adcyap1⁺ neurons as key integrative node in energy balance and reveal brainstem-derived circuits with potential for more precise and better tolerated anti-obesity interventions. It also highlights the potential of targeting Gfral+ neurons to curb involuntary weight loss during certain inflammatory conditions.