Distinct Hindbrain GLP1R Circuits Control Satiety and Aversion in Obesity Therapeutics

Core Concepts

Hindbrain GLP1R neurons are required for the efficacy of GLP1-based obesity drugs, but their subpopulations are tuned to either nutritive or aversive stimuli, enabling selective targeting to promote weight loss while avoiding adverse side effects.

Abstract

The article investigates the brain circuits that link satiety to aversion in the context of obesity therapeutics targeting the glucagon-like peptide-1 receptor (GLP1R). The key findings are: Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons showed that most neurons are tuned to either nutritive or aversive stimuli, but not both. Nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli and trigger satiety in the absence of aversion, whereas area postrema (AP) GLP1R neurons are broadly responsive and trigger strong aversion with food intake reduction. Anatomical and behavioral analyses revealed that NTS GLP1R and AP GLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists can reduce food intake even when the aversion pathway is inhibited, suggesting that targeting NTS GLP1R neurons could promote weight loss while avoiding the adverse side effects that limit treatment adherence.

Stats

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting. GLP1R agonists reduce food intake even when the aversion pathway is inhibited.

Quotes

"Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction." "Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited."

Key Insights Distilled From

Dissociable hindbrain GLP1R circuits for satiety and aversion - Nature

by Kuei-Pin Hua... at www.nature.com 07-10-2024

https://www.nature.com/articles/s41586-024-07685-6

Deeper Inquiries

What are the potential mechanisms underlying the functional separation of satiety and aversion circuits mediated by hindbrain GLP1R neurons?

The functional separation of satiety and aversion circuits mediated by hindbrain GLP1R neurons can be attributed to the distinct tuning of these neurons to either nutritive or aversive stimuli. Through systematic investigation, it was found that hindbrain GLP1R neurons are specialized to respond to specific stimuli, with most neurons being dedicated to either promoting satiety or inducing aversive responses, but not both simultaneously. Additionally, the differential responsiveness of area postrema (AP) GLP1R neurons and nucleus of the solitary tract (NTS) GLP1R neurons further contributes to this functional separation. APGLP1R neurons are broadly responsive and trigger strong aversion with food intake reduction, while NTSGLP1R neurons are biased towards nutritive stimuli and induce satiety without aversive effects. These distinct response profiles suggest that hindbrain GLP1R neurons are organized in a manner that allows for separate regulation of satiety and aversion pathways.

How could the selective targeting of NTS GLP1R neurons be leveraged to develop more effective and better-tolerated obesity treatments?

The selective targeting of NTSGLP1R neurons presents a promising strategy for developing more effective and better-tolerated obesity treatments. By specifically activating NTSGLP1R neurons, it is possible to trigger satiety without the aversive side effects commonly associated with GLP1R agonists. This targeted approach could lead to the development of obesity therapeutics that promote weight loss through the activation of satiety pathways while minimizing or eliminating the adverse effects that hinder treatment adherence. By focusing on NTSGLP1R neurons, researchers and pharmaceutical companies can potentially design drugs that selectively modulate satiety signals, offering a more tolerable and efficient treatment option for obesity.

What other neural circuits or neuromodulatory systems might be involved in regulating the balance between satiety and aversion, and how could this knowledge be applied to improve obesity therapies?

In addition to hindbrain GLP1R circuits, several other neural circuits and neuromodulatory systems are likely involved in regulating the balance between satiety and aversion. For instance, the hypothalamus, a key brain region involved in appetite regulation, may interact with hindbrain GLP1R neurons to modulate feeding behavior. Neuromodulators such as dopamine, serotonin, and endocannabinoids also play crucial roles in appetite control and reward processing, potentially influencing the balance between satiety and aversion. Understanding the interactions between these different neural circuits and neuromodulatory systems could provide valuable insights for improving obesity therapies. By targeting specific pathways that regulate appetite and aversion, researchers may develop more precise and effective treatments that address the complex mechanisms underlying obesity while minimizing unwanted side effects.