Lateral Septum Neurons Are Where Liraglutide Works to Suppress Appetite in Mice | Research

The takeaway

GLP-1 receptor neurons in the lateral septum, not the hypothalamus, are critical for liraglutide's appetite-suppressing and weight-loss effects in mice.

LS knockdown blocks liraglutide; hypothalamus knockdown does not
Removing GLP-1 receptors from the lateral septum substantially reduced liraglutide's effects on feeding and weight, while removing them from the hypothalamus did not — a surprising finding that redefines where this drug works.

What the researchers found

GLP-1 receptor-positive neurons in the lateral septum (LSGLP-1R) were robustly activated by liraglutide. Chemogenetic activation of these neurons dramatically suppressed feeding. Critically, targeted knockdown of GLP-1 receptors in the lateral septum — but not in the hypothalamus — substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, and synaptic inactivation of these neurons diminished liraglutide's anorexic effects.

Why it matters

This study fundamentally shifts understanding of where GLP-1 drugs work in the brain. The hypothalamus has long been considered the primary appetite center, but this research shows the lateral septum is actually the critical site for liraglutide's effects. This has major implications for developing next-generation GLP-1 peptide drugs that could be designed to target the lateral septum more specifically, potentially improving efficacy or reducing side effects.

How the study worked

Mouse study using multiple neuroscience techniques: chemogenetics (DREADDs) to artificially activate or silence specific neurons, targeted gene knockdown to remove GLP-1 receptors from specific brain regions, calcium imaging to record neuron activity during feeding, and synaptic inactivation to test whether neuronal connections are required for liraglutide's effects.

What this study cannot tell us

This is a mouse study, and the relative importance of the lateral septum versus other brain regions may differ in humans. The techniques used (chemogenetics, targeted knockdown) are powerful but not perfectly specific. Liraglutide was the only GLP-1 agonist tested, and other drugs in the class (semaglutide, tirzepatide) may have different brain region dependencies. Long-term metabolic effects beyond acute feeding suppression were not extensively characterized.

How to read the evidence

This is a rigorous preclinical mechanistic study using multiple complementary neuroscience techniques, published in the high-impact Journal of Clinical Investigation. While compelling in mice, translation to human neurobiology requires further validation.

When this study was published

Published in 2024 in JCI, this is very recent and represents a significant advance in understanding GLP-1 drug mechanisms. It builds on and challenges previous hypothalamus-focused research.

The bigger picture

Published in the Journal of Clinical Investigation — one of the most prestigious medical research journals — this study represents a paradigm shift in GLP-1 neuroscience. The discovery that the lateral septum, rather than the hypothalamus, is critical for liraglutide's pharmacological effects challenges decades of assumptions about appetite regulation and could redirect drug development efforts for the entire GLP-1 drug class.

Questions still open

Do other GLP-1 agonists like semaglutide also primarily act through lateral septum neurons?
Is the lateral septum similarly important for GLP-1 drug effects in humans?
Could targeting GLP-1 drug delivery specifically to the lateral septum improve weight loss efficacy?

Common questions

Why is it surprising that the lateral septum is more important than the hypothalamus?

The hypothalamus has been considered the brain's 'appetite center' for decades. Most research on how GLP-1 drugs suppress appetite has focused on hypothalamic neurons. This study shows that when GLP-1 receptors are removed specifically from the hypothalamus, liraglutide still works — but when removed from the lateral septum, it stops working. This unexpected finding redirects the field's understanding of these drugs.

What does this mean for people currently taking GLP-1 drugs like Ozempic or Wegovy?

For current patients, the practical implications are minimal — the drugs work regardless of which brain region is responsible. But for future drug development, this is important because it suggests that drugs designed to specifically target lateral septum GLP-1 receptors could potentially be more effective or have fewer side effects than current drugs that act broadly across the brain.

Read the original research

GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

The Journal of clinical investigation, 134(17)

View on PubMed ↗Publisher’s paper ↗

Citation

Chen, Zijun; Deng, Xiaofei; Shi, Cuijie; Jing, Haiyang; Tian, Yu; Zhong, Jiafeng; Chen, Gaowei; Xu, Yunlong; Luo, Yixiao; Zhu, Yingjie. (2024). GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.. The Journal of clinical investigation, 134(17). https://doi.org/10.1172/JCI178239