Breakthrough discovery of TRH neurons’ role in appetite suppression opens new doors for targeted and effective obesity therapies.
Study: Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety. Image Credit: GrAl / ShutterstockStudy: Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety. Image Credit: GrAl / Shutterstock
A recent study published in the journal Nature Metabolism explored the neural mechanisms through which glucagon-like peptide 1 (GLP-1) receptor agonists, such as liraglutide, suppress appetite and promote weight loss.
By integrating molecular mapping techniques, the researchers identified specific hypothalamic neural circuits and neurons that inhibit the hunger-driving Agouti-related peptide (AgRP) neurons, revealing critical pathways and additional therapeutic targets for appetite regulation and obesity management.
Background
Researchers discovered that TRHArc neurons regulate feeding through fast neurotransmitter-mediated inhibition, contrasting with delayed peptidergic signaling, highlighting their rapid impact on appetite suppression.
Obesity remains one of the major global health concerns, with limited effective and sustainable treatment options. GLP-1 receptor agonists, which have been widely used as anti-obesity medications, have demonstrated potent appetite-suppressing effects, but their precise neural mechanisms are not well known.
Existing research suggests the arcuate nucleus (Arc) of the hypothalamus is a critical center for appetite regulation, housing the AgRP neurons that strongly promote feeding behavior. GLP-1 receptors are expressed in various brain and peripheral regions, but evidence suggests that Arc-localized GLP-1 receptors play a pivotal and distinct role in mediating appetite suppression.
Despite these findings, the specific neuronal subtypes and circuits involved in appetite suppression remain unclear, especially those inhibiting AgRP neurons. Advanced molecular tools, such as single-cell transcriptomics and viral tracing, provide opportunities to map these complex interactions. Moreover, bridging this knowledge gap could advance obesity therapies by pinpointing more precise and effective neural targets while reducing adverse effects.
About the Study
In the present study, a team of neuroscientists explored the neural circuits underlying GLP-1 receptor agonist-induced appetite suppression using a combination of molecular mapping and functional neuroscience techniques. They developed the innovative RAMPANT method (Rabies Afferent Mapping by Poly-A Nuclear Transcriptomics) to identify neurons connected to AgRP cells in the Arc of the hypothalamus. Furthermore, using adeno-associated viruses and rabies-based tracing in AgRP-controlled mice models, they labeled and characterized the synaptic inputs to AgRP neurons.
The study focused on three hypothalamic regions — Arc, paraventricular hypothalamus (PVH), and dorsomedial hypothalamus (DMH). The researchers isolated the nuclei from these areas for single-nucleus ribonucleic acid (RNA) sequencing to profile transcriptomic markers.
TRHArc neurons were shown to reduce hyperphagia (excessive hunger) even in the absence of GLP-1 receptor agonists, suggesting their potential as standalone targets for obesity treatment.
Additionally, the study identified transcriptionally distinct neuron subtypes, including neurons associated with the thyrotropin-releasing hormone (TRH) in the Arc, known as TRHArc neurons, which express GLP-1 receptors and have inhibitory effects on AgRP neurons. To confirm these interactions, the researchers performed channelrhodopsin-assisted circuit mapping in genetically modified mice to demonstrate functional synaptic inhibition by TRHArc neurons. These findings were further validated using RNA fluorescence in situ hybridization to identify key molecular markers of these neurons. This combined approach offered unprecedented precision in mapping neuron subtypes and their roles.
Furthermore, functional studies were employed to test the role of TRHArc neurons in feeding behavior. The researchers also used optogenetics, where light is used to control the activity of cells such as neurons, to selectively activate TRHArc neurons and measure their effects on food intake in fasted and free-fed mice. Additionally, calcium imaging assessed the direct activation of TRHArc neurons by liraglutide.
Finally, by genetically silencing TRHArc neurons, the researchers also examined their involvement in liraglutide's appetite-suppressing and weight-reducing effects.
Results
The researchers observed that TRHArc neurons are key mediators of the appetite-suppressing effects of liraglutide. These neurons directly inhibit AgRP neurons in the Arc, a population known to drive feeding behavior. Using rabies-based tracing combined with single-cell transcriptomics, the team identified that TRHArc neurons are a critical afferent subtype of AgRP neurons. They are characterized by their expression of thyrotropin-releasing hormone and GLP-1 receptors.
Furthermore, the optogenetic activation of TRHArc neurons resulted in reduced food intake in fasted and fed mice, demonstrating their role in suppressing feeding. Synaptic mapping also confirmed that TRHArc neurons inhibit AgRP neurons through inputs related to the neurotransmitter gamma-aminobutyric acid (GABA).
Functional experiments demonstrated that TRHArc neurons not only suppress feeding but also regulate body weight under metabolic challenges, showcasing their broader role in energy balance.
Moreover, calcium imaging revealed that liraglutide directly activates TRHArc neurons, significantly increasing their activity. Functional experiments further indicated that silencing TRHArc neurons diminished the ability of liraglutide to suppress appetite and body weight, highlighting the necessity of these neurons for the drug's full therapeutic effects.
Additionally, the researchers found that TRHArc neurons also regulate feeding independent of liraglutide, suggesting their broader role in appetite control.
The study confirmed that TRHArc neurons influence feeding primarily through fast neurotransmitter-mediated inhibition rather than delayed peptidergic signaling, where neurotransmitters are activated by short peptide chains. This distinction may refine future therapeutic strategies targeting hunger suppression.
Moreover, TRHArc neuron activity was shown to suppress AgRP neuron-driven hyperphagia, or insatiable hunger, establishing a direct mechanistic link between these two neuron populations in regulating energy balance.
Conclusions
Overall, the study revealed TRHArc neurons as critical mediators of GLP-1 receptor agonist-induced appetite suppression and weight reduction. By directly inhibiting hunger-promoting AgRP neurons, these neurons were found to play a pivotal role in regulating energy balance.
The findings provide valuable insights into the neural circuits underlying obesity therapies and pave the way for developing more precise and potentially side-effect-minimized interventions. The researchers believe future research could further elucidate additional pathways and mechanisms to refine and enhance obesity treatment strategies.
Journal reference:
Webster, A. N., Becker, J. J., Li, C., Schwalbe, D. C., Kerspern, D., Karolczak, E. O., Bundon, C. B., Onoharigho, R. A., Crook, M., Jalil, M., Godschall, E. N., Dame, E. G., Dawer, A., Matthew, D., Pers, T. H., Lutas, A., Habib, N., Güler, A. D., Krashes, M. J., . . . Campbell, J. N. (2024). Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety. Nature Metabolism, 1-20. DOI: 10.1038/s42255-024-01168-8, https://www.nature.com/articles/s42255-024-01168-8