New analysis reveals that liraglutide, a GLP-1 receptor agonist, crosses the blood-brain barrier to focus on particular neurons, lowering urge for food and selling lasting weight reduction.
Research: The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight reduction. Picture Credit score: Peter Togel / Shutterstock
In a current research printed in The Journal of Medical Investigation, researchers used a number of cutting-edge in vivo, ex vivo, and in vitro methodologies to elucidate the mechanisms underpinning liraglutide’s weight reduction, hitherto unknown to science.
Liraglutide, a comparatively novel incretin mimetic from the glucagon-like peptide-1 (GLP-1) analog class of anti-obesity and anti-type 2 diabetes (T2D) drugs, has been beforehand reported to lead to vital weight discount in sufferers. Nonetheless, its exact mode of motion and relationship with the mind weren’t absolutely understood.
The current research reveals that liraglutide reveals region-specific interactions with GLP–1–producing neurons. Though liraglutide prompts GLP-1 receptors within the mind, the drug’s weight reduction results are unbiased of GLP-1R exercise within the hindbrain, space postrema, vagus nerve, and paraventricular nucleus. Whereas GLP-1R exercise is noticed in these areas, they aren’t major mediators of weight discount. As an alternative, GLP-1R in particular hypothalamic areas, notably within the arcuate nucleus (ARC), is required for liraglutide’s uptake by the mind.
Notably, outcomes spotlight that neurons certain to liraglutide within the ARC expressed cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC), although POMC expression was unaffected by liraglutide remedy. GLP-1R on these CART-expressing ARC neurons suppresses urge for food, leading to vital, long-lasting weight reduction.
Identification of weight loss-mediating liraglutide targets
Background
Obese and weight problems (physique mass index [BMI] ≥ 25 and 30 kg/m2, respectively) are public well being considerations with world protection and alarmingly rising prevalence. Estimates counsel that 12.5% of all people lived with weight problems in 2022, doubling (for adults) and quadrupling (for adolescents) weight problems studies from 1990.
Extreme physique weight has been linked to a bunch of comorbidities, together with diabetes, cardiovascular illnesses (CVDs), cancers, intestine metabolite imbalances, and elevated susceptibility to pathogen-derived infections.
Regardless of many years of intensive analysis to determine or develop therapeutics to handle weight reduction stably, the molecular mechanisms underpinning urge for food and gas metabolism stay advanced and aren’t absolutely understood.
Current advances in neurophysiology and pharmacotherapy have resulted within the discovery of peripheral peptide (incretin) hormones, such because the glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptides (GIPs).
Initially developed as anti-diabetes interventions, these incretins have demonstrated long-term weight reduction in medical settings. Nonetheless, the diploma to which they have an effect on mind capabilities associated to urge for food management and sugar homeostasis has remained elusive.
“New brokers being thought of for the remedy of weight problems are analogs of the peripheral peptide hormones, like glucagon-like peptide-1 (GLP-1), peptide YY, and glucagon, and a few are antagonists for receptors, just like the ghrelin receptor. These hormones are a part of the gut-brain axis, and their respective receptors are sometimes current within the periphery in addition to within the mind.”
Elucidating the pathways and processes by which GLP-1 and related hormones modulate weight reduction might permit for the finetuning and evolution of novel therapeutic interventions towards weight problems, which, if left unchecked, is anticipated to impression greater than half the world’s human inhabitants by 2035.
In regards to the research
The current research leverages cutting-edge in vitro, in vivo, and ex vivo assays to analyze the mechanisms permitting liraglutide, a GLP-1 receptor (GLP-1R) agonist, to scale back customers’ weight and urge for food considerably.
Experimental procedures included surgical procedure fashions comparable to subdiaphragmatic vagal deafferentation (SDA), particular ablation of the world postrema (AP), and paraventricular nucleus (PVN) lesions, all of which had been performed on Sprague-Dawley (SPDR) rats.
Moreover, exendin (a GLP-1R agonist) assays (central and peripheral administration), mRNA central nervous system (CNS) evaluation, immunohistochemistry, and fluorescently labeled liraglutide assays had been performed.
Collectively, these methodologies had been used to determine the region-specific uptake of liraglutide throughout particular mind areas and assess how GLP-1R agonists modulate neuronal pathways related to urge for food management. Electrophysiology experiments additional 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 starvation alerts.
Lastly, double in situ hybridization and electrophysiology investigations (in homozygous Npy-hrGFP C57BL/6J background male mice) had been used to determine genetic sequences related within the liraglutide-enhanced mind pathways and the differential transmission of neural impulses (probably related to urge for food and satiation) within the presence of this and related GLP-1R agonists. The dosage of liraglutide was normalized to 200 μg/kg, injected subcutaneously bidaily (BID).
Research findings
Liraglutide remedy was noticed to scale back SPDR weight acquire by 10% over 14 days. Nonetheless, investigations of the AP and vagal nerve neurons revealed that the appetite-lowering results of the drug (liraglutide) had been unbiased of the GLP-1R in these cells. In actual fact, these areas displayed GLP-1R exercise, however liraglutide’s impact on weight reduction was mediated elsewhere. As an alternative, diet-induced overweight (DIO) rat assays (28 days) revealed that liraglutide regulates the neuronal expression of CART and POMC in ARC neurons, with elevated CART ranges however unchanged POMC expression. Fluorescent probe experiments revealed that peripherally administered liraglutide crossed the blood-brain barrier (BBB) and accessed the mind straight, primarily focusing on neurons within the ARC.
Electrophysiology research additional revealed that GLP-1 agonists like liraglutide inhibit the exercise of NPY/AgRP neurons by way of GABA signaling, thereby suppressing hunger-related impulses.
“In hypothalamic ARC neurons, liraglutide seemed to be internalized, as in pancreatic β cells, suggesting that GLP-1R is also internalized with an agonist ligand in neurons. Though tougher to discriminate in neurons, exendin(9-39) appeared to not be internalized in neurons within the ARC both, as was noticed with the antagonist in β cells.”
Lastly, a comparative evaluation utilizing exendin(9-39) to dam GLP-1R within the ARC confirmed that antagonizing the ARC, slightly than the PVN, considerably diminished liraglutide’s weight-loss results, confirming the ARC as the first goal for long-term weight discount.
Conclusions
The current research elucidates novel mechanistic and transcriptomic pathways enabling the weight-reducing results of liraglutide remedy in overweight mice. It highlights the power of peripheral liraglutide to cross the BBB and particularly goal hypothalamic ARC cells, eliciting vital urge for food suppression and subsequent weight reduction.
Moreover, the research means that whereas liraglutide impacts each POMC and NPY/AgRP neurons, its weight reduction results are primarily pushed by CART signaling and GABA-mediated inhibition of starvation pathways.
Whereas extra analysis is required to judge the drug’s unwanted side effects and people of comparable GLP-1R agonists, these findings type the idea for growing the following technology of anti-weight-gain therapeutics.
Conflicts of curiosity
Novo Nordisk markets liraglutide for the remedy of diabetes. A number of authors are full-time workers of Novo Nordisk and maintain minor shares. Moreover, two authors seek the advice of for and obtain analysis funding from Novo Nordisk, whereas one other serves as a guide.
Journal reference:
- Secher, A., Jelsing, J., Baquero, A. F., Hecksher-Sørensen, J., Cowley, M. A., Dalbøge, L. S., Hansen, G., Grove, Ok. L., Pyke, C., Raun, Ok., Schäffer, L., Tang-Christensen, M., Verma, S., Witgen, B. M., Vrang, N., & Bjerre Knudsen, L. (2014). The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight reduction. In Journal of Medical Investigation (Vol. 124, Concern 10, pp. 4473–4488). American Society for Medical Investigation, DOI – 10.1172/jci75276, https://www.jci.org/articles/view/75276
