Obesity stands as one major global health issue, with limited effective and sustainable treatment options. Lately-introduced 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 still incompletely elucidated. 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 this phenomenon remain unclear, especially those inhibiting AgRP neurons. Advanced molecular tools, provide opportunities to map these complex interactions.
In addition, bridging this knowledge gap could advance obesity therapies by pinpointing more precise and effective neural targets while reducing adverse effects. 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. In the specific, TRH+ Arc neurons regulate feeding through fast neurotransmitter-mediated inhibition, contrasting with delayed peptidergic signaling, highlighting their rapid impact on appetite suppression.
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 transcriptomic-based) and functional neuroscience techniques (adeno-associated virus). Thyrotropin-releasing hormone positive (TRH+) Arc 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 TRH in the Arc, which express GLP-1 receptors and have inhibitory effects on AgRP neurons. To confirm these interactions, the researchers performed channel rhodopsin-assisted circuit mapping in genetically modified mice to demonstrate functional synaptic inhibition by TRH+ Arc 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. By additionally employng 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. They could pinpoint the calcium currents as the main mediator of the liraglutida activity on TRH+ Arc neurons. 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 TRH 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). The investigation confirmed that TRH+ Arc neurons influence feeding primarily through fast neurotransmitter-mediated inhibition rather than delayed peptidergic signaling, where neurotransmitters are activated by neuropeptides. This distinction may refine therapeutic adjustments 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. Overall, these data provide valuable insights into the neural circuits underlying obesity therapies, paving more precise and potentially side-effect-minimized interventions.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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