Liraglutide activates key brain circuits to trigger weight loss in obesity

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Sep 23 2024

New research reveals that liraglutide, a GLP-1 receptor agonist, crosses the blood-brain barrier to target specific neurons, reducing appetite and promoting lasting weight loss.

Study: The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Image Credit: Peter Togel / Shutterstock

In a recent study published in The Journal of Clinical Investigation, researchers used multiple cutting-edge in vivo, ex vivo, and in vitro methodologies to elucidate the mechanisms underpinning liraglutide’s weight loss, hitherto unknown to science.

Liraglutide, a relatively novel incretin mimetic from the glucagon-like peptide-1 (GLP-1) analog class of anti-obesity and anti-type 2 diabetes (T2D) medications, has been previously reported to result in significant weight reduction in patients. However, its precise mode of action and relationship with the brain were not fully understood.

The present study reveals that liraglutide exhibits region-specific interactions with GLP–1–producing neurons. Although liraglutide activates GLP-1 receptors in the brain, the drug's weight loss effects are independent of GLP-1R activity in the hindbrain, area postrema, vagus nerve, and paraventricular nucleus. While GLP-1R activity is observed in these regions, they are not primary mediators of weight reduction. Instead, GLP-1R in specific hypothalamic regions, particularly in the arcuate nucleus (ARC), is required for liraglutide’s uptake by the brain.

Notably, results highlight that neurons bound to liraglutide in the ARC expressed cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC), though POMC expression was unaffected by liraglutide treatment. GLP-1R on these CART-expressing ARC neurons suppresses appetite, resulting in significant, long-lasting weight loss.

Background

Overweight and obesity (body mass index [BMI] ≥ 25 and 30 kg/m², respectively) are public health concerns with global coverage and alarmingly increasing prevalence. Estimates suggest that 12.5% of all humans lived with obesity in 2022, doubling (for adults) and quadrupling (for adolescents) obesity reports from 1990.

Excessive body weight has been linked to a host of comorbidities, including diabetes, cardiovascular diseases (CVDs), cancers, gut metabolite imbalances, and increased susceptibility to pathogen-derived infections.

Despite decades of intensive research to identify or develop therapeutics to manage weight loss stably, the molecular mechanisms underpinning appetite and fuel metabolism remain complex and are not fully understood.

Recent advances in neurophysiology and pharmacotherapy have resulted in the discovery of peripheral peptide (incretin) hormones, such as the glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptides (GIPs).

Originally developed as anti-diabetes interventions, these incretins have demonstrated long-term weight loss in clinical settings. However, the degree to which they affect brain functions related to appetite control and sugar homeostasis has remained elusive.

“New agents being considered for the treatment of obesity are analogs of the peripheral peptide hormones, like glucagon-like peptide-1 (GLP-1), peptide YY, and glucagon, and some are antagonists for receptors, like the ghrelin receptor. These hormones are part of the gut-brain axis, and their respective receptors are often present in the periphery as well as in the brain.”

Elucidating the pathways and processes through which GLP-1 and similar hormones modulate weight loss may allow for the finetuning and evolution of novel therapeutic interventions against obesity, which, if left unchecked, is expected to impact more than half the world’s human population by 2035.

About the study

The present study leverages cutting-edge in vitro, in vivo, and ex vivo assays to investigate the mechanisms allowing liraglutide, a GLP-1 receptor (GLP-1R) agonist, to reduce users’ weight and appetite significantly.

Experimental procedures included surgery models such as subdiaphragmatic vagal deafferentation (SDA), specific ablation of the area postrema (AP), and paraventricular nucleus (PVN) lesions, all of which were conducted on Sprague-Dawley (SPDR) rats.

Additionally, exendin (a GLP-1R agonist) assays (central and peripheral administration), mRNA central nervous system (CNS) analysis, immunohistochemistry, and fluorescently labeled liraglutide assays were conducted.

Together, these methodologies were used to identify the region-specific uptake of liraglutide across specific brain regions and assess how GLP-1R agonists modulate neuronal pathways associated with appetite control. Electrophysiology experiments further demonstrated that GLP-1R activation led to depolarization of POMC neurons and inhibition of NPY/AgRP neurons, mediated by GABAergic signaling, explaining the suppression of hunger signals.

Finally, double in situ hybridization and electrophysiology investigations (in homozygous Npy-hrGFP C57BL/6J background male mice) were used to identify genetic sequences relevant in the liraglutide-enhanced brain pathways and the differential transmission of neural impulses (potentially associated with appetite and satiation) in the presence of this and similar GLP-1R agonists.  The dosage of liraglutide was normalized to 200 μg/kg, injected subcutaneously bidaily (BID).

Study findings

Liraglutide treatment was observed to reduce SPDR weight gain by 10% over 14 days. However, investigations of the AP and vagal nerve neurons revealed that the appetite-lowering effects of the drug (liraglutide) were independent of the GLP-1R in these cells. In fact, these regions displayed GLP-1R activity, but liraglutide’s effect on weight loss was mediated elsewhere. Instead, diet-induced obese (DIO) rat assays (28 days) revealed that liraglutide regulates the neuronal expression of CART and POMC in ARC neurons, with increased CART levels but unchanged POMC expression. Fluorescent probe experiments revealed that peripherally administered liraglutide crossed the blood-brain barrier (BBB) and accessed the brain directly, primarily targeting neurons in the ARC.

Electrophysiology studies further revealed that GLP-1 agonists like liraglutide inhibit the activity of NPY/AgRP neurons via GABA signaling, thereby suppressing hunger-related impulses.

“In hypothalamic ARC neurons, liraglutide appeared to be internalized, as in pancreatic β cells, suggesting that GLP-1R also is internalized with an agonist ligand in neurons. Although more difficult to discriminate in neurons, exendin(9-39) appeared not to be internalized in neurons in the ARC either, as was observed with the antagonist in β cells.”

Finally, a comparative analysis using exendin(9-39) to block GLP-1R in the ARC showed that antagonizing the ARC, rather than the PVN, significantly reduced liraglutide's weight-loss effects, confirming the ARC as the primary target for long-term weight reduction.

Conclusions

The present study elucidates novel mechanistic and transcriptomic pathways enabling the weight-reducing effects of liraglutide treatment in obese mice. It highlights the ability of peripheral liraglutide to cross the BBB and specifically target hypothalamic ARC cells, eliciting significant appetite suppression and subsequent weight loss.

Furthermore, the study suggests that while liraglutide impacts both POMC and NPY/AgRP neurons, its weight loss effects are primarily driven by CART signaling and GABA-mediated inhibition of hunger pathways.

While additional research is required to evaluate the drug's side effects and those of similar GLP-1R agonists, these findings form the basis for developing the next generation of anti-weight-gain therapeutics.

Conflicts of interest

Novo Nordisk markets liraglutide for the treatment of diabetes. Several authors are full-time employees of Novo Nordisk and hold minor shares. Additionally, two authors consult for and receive research funding from Novo Nordisk, while another serves as a consultant.