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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Vydáno v:	JCI insight Ročník 5; číslo 6
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 26.03.2020
Témata:	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
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: SG, CGS, and SJP contributed equally to the work.
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.133429