The brain's hunger switch: TRH neurons are key to treating obesity

The brain's hunger switch: TRH neurons are key to treating obesity

Groundbreaking discovery of the role of TRH neurons in appetite suppression opens new possibilities for targeted and effective anti-obesity therapies.

A study recently published in the journalNatural metabolismexplored the neural mechanisms by which glucagon-like peptide-1 receptor agonists (GLP-1) such as liraglutide suppress appetite and promote weight loss.

By integrating molecular mapping techniques, researchers identified specific hypothalamic neural circuits and neurons that inhibit hunger-driving agouti-related peptide (AgRP) neurons, uncovering critical signaling pathways and additional therapeutic targets for appetite regulation and obesity management.

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The researchers found that TRHArc neurons regulate food intake through rapid neurotransmitter-mediated inhibition, as opposed to delayed peptidic signaling, highlighting their rapid effect on appetite suppression.

Obesity remains one of the largest global health problems with limited effective and sustainable treatment options. GLP-1 receptor agonists, commonly used as anti-obesity drugs, have shown potent appetite-suppressing effects, but their exact neural mechanisms are not well understood.

Existing research suggests that the arcuate nucleus (Arc) of the hypothalamus is a critical center for appetite regulation and houses the AgRP neurons, which strongly promote feeding behavior. GLP-1 receptors are expressed in various brain and peripheral regions, but there is evidence that Arc-localized GLP-1 receptors play a critical and distinct role in mediating appetite suppression.

Despite these findings, the specific neuronal subtypes and circuits involved in appetite suppression remain unclear, particularly those that inhibit AgRP neurons. Advanced molecular tools such as single-cell transcriptomics and virus tracking provide opportunities to map these complex interactions. Furthermore, bridging this knowledge gap could advance obesity therapies by identifying more precise and effective neural targets while reducing side effects.

About the study

In the present study, a team of neuroscientists used a combination of molecular mapping and functional neuroscience techniques to investigate the neural circuits underlying appetite suppression induced by GLP-1 receptor agonists. They developed the innovative RAMPANT (Rabies Afferent Mapping by Poly-A Nuclear Transcriptomics) method to identify neurons connected to AgRP cells in the arch of the hypothalamus. In addition, they labeled and characterized the synaptic inputs to AgRP neurons using adeno-associated viruses and rabies-based tracking in AgRP-controlled mouse models.

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 have been shown to reduce hyperphagia (excessive hunger) even in the absence of GLP-1 receptor agonists, suggesting their potential as stand-alone targets for the treatment of obesity.

In addition, the study identified transcriptionally distinct neuron subtypes, including neurons associated with thyrotropin-releasing hormone (TRH) in the Arc, called 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 results were further validated using RNA fluorescence in situ hybridization to identify key molecular markers of these neurons. This combined approach provided unprecedented precision in mapping neuron subtypes and their roles.

In addition, functional studies were performed to test the role of TRHArc neurons in feeding behavior. The researchers also used optogenetics, which uses light 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. In addition, calcium imaging examined the direct activation of TRHArc neurons by liraglutide.

Finally, by genetically silencing TRHArc neurons, the researchers also examined their involvement in the appetite-suppressing and weight-reducing effects of liraglutide.

Results

The researchers observed that TRHArc neurons are important mediators of the appetite-suppressing effects of liraglutide. These neurons directly inhibit AgRP neurons in the Arc, a population known to control 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 the expression of thyrotropin-releasing hormone and GLP-1 receptors.

Furthermore, optogenetic activation of TRHArc neurons resulted in reduced food intake in fasted and fed mice, demonstrating their role in suppressing food intake. Synaptic mapping also confirmed that TRHArc neurons inhibit AgRP neurons through inputs related to the neurotransmitter gamma-aminobutyric acid (GABA).

Functional experiments showed that TRHArc neurons not only suppress food intake but also regulate body weight during metabolic challenges, highlighting their broader role in energy balance.

In addition, calcium imaging revealed that liraglutide directly activates TRHArc neurons and significantly increases their activity. Functional experiments also showed that silencing TRHArc neurons reduced liraglutide's ability to suppress appetite and body weight, highlighting the necessity of these neurons for the drug's full therapeutic effect.

Additionally, the researchers found that TRHArc neurons also regulate food intake independently of liraglutide, suggesting their broader role in appetite control.

The study confirmed that TRHArc neurons influence food intake primarily through rapid neurotransmitter-mediated inhibition rather than delayed peptide signaling, in which neurotransmitters are activated by short peptide chains. This distinction could refine future therapeutic strategies to suppress hunger.

Furthermore, the activity of TRHArc neurons has been shown to suppress hyperphagia or insatiable hunger caused by AgRP neurons, thus providing a direct mechanistic link between these two neuronal populations in regulating energy balance.

Conclusions

Overall, the study demonstrated that TRHArc neurons are 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 critical role in regulating energy balance.

The results provide valuable insights into the neural circuits underlying obesity therapies and pave the way for the development of more precise and potentially side-effect minimizing interventions. The researchers believe future research could further elucidate additional pathways and mechanisms to refine and improve obesity treatment strategies.

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