Semaglutide lowers body weight in rodents via distributed neural pathways

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here sh...

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Published in:JCI insight Vol. 5; no. 6
Main Authors: Gabery, Sanaz, Salinas, Casper G., Paulsen, Sarah J., Ahnfelt-Rønne, Jonas, Alanentalo, Tomas, Baquero, Arian F., Buckley, Stephen T., Farkas, Erzsébet, Fekete, Csaba, Frederiksen, Klaus S., Helms, Hans Christian C., Jeppesen, Jacob F., John, Linu M., Pyke, Charles, Nøhr, Jane, Lu, Tess T., Polex-Wolf, Joseph, Prevot, Vincent, Raun, Kirsten, Simonsen, Lotte, Sun, Gao, Szilvásy-Szabó, Anett, Willenbrock, Hanni, Secher, Anna, Knudsen, Lotte Bjerre
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 26.03.2020
Subjects:
Ablation
Animals
Area postrema
Blood-brain barrier
Body Weight - drug effects
Brain
Brain - drug effects
Brain stem
c-Fos protein
Cardiovascular diseases
Clinical trials
Diabetes
Diabetes mellitus
Eating - drug effects
Energy expenditure
Energy intake
Energy Metabolism - drug effects
Food
Food intake
Food preferences
Glucagon
Glucagon-like peptide 1
Glucagon-Like Peptide-1 Receptor - drug effects
Glucagon-Like Peptides - pharmacology
Hindbrain
Homeostasis
Hypothalamus
Mice
Neural networks
Neural Pathways - drug effects
Obesity
Parabrachial nucleus
Peptides
Prolactin
Rats
Regulatory approval
Reinforcement
Thyrotropin-releasing hormone
Transcriptomics
Tyrosine 3-monooxygenase
Ventricles (cerebral)
Weight
Weight control
Neuroimaging
Obesity
Neuroscience
Metabolism
Mouse models
ISSN:2379-3708, 2379-3708
Online Access:Get full text
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Summary:Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.
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Authorship note: SG, CGS, and SJP contributed equally to the work.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.133429