Semaglutide lowers body weight in rodents via distributed neural pathways
Sanaz Gabery, Casper G. Salinas, Sarah J. Paulsen, Jonas Ahnfelt-Rønne, Tomas Alanentalo, Arian F. Baquero, Stephen T. Buckley, Erzsébet Farkas, Csaba Fekete, Klaus S. Frederiksen, Wouter Frederik Johan Hogendorf, Hans Christian C. Helms, Jacob F. Jeppesen, Linu M. John, Charles Pyke, Jane Nøhr, Tess T. Lu, Joseph Polex-Wolf, Vincent Prevot, Kirsten Raun, Lotte Simonsen, Gao Sun, Anett Szilvásy-Szabó, Hanni Willenbrock, Anna Secher, Lotte Bjerre Knudsen
Sanaz Gabery, Casper G. Salinas, Sarah J. Paulsen, Jonas Ahnfelt-Rønne, Tomas Alanentalo, Arian F. Baquero, Stephen T. Buckley, Erzsébet Farkas, Csaba Fekete, Klaus S. Frederiksen, Wouter Frederik Johan Hogendorf, Hans Christian C. Helms, Jacob F. Jeppesen, Linu M. John, Charles Pyke, Jane Nøhr, Tess T. Lu, Joseph Polex-Wolf, Vincent Prevot, Kirsten Raun, Lotte Simonsen, Gao Sun, Anett Szilvásy-Szabó, Hanni Willenbrock, Anna Secher, Lotte Bjerre Knudsen
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Research Article Metabolism Neuroscience

Semaglutide lowers body weight in rodents via distributed neural pathways

Abstract

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.

Authors

Sanaz Gabery, Casper G. Salinas, Sarah J. Paulsen, Jonas Ahnfelt-Rønne, Tomas Alanentalo, Arian F. Baquero, Stephen T. Buckley, Erzsébet Farkas, Csaba Fekete, Klaus S. Frederiksen, Wouter Frederik Johan Hogendorf, Hans Christian C. Helms, Jacob F. Jeppesen, Linu M. John, Charles Pyke, Jane Nøhr, Tess T. Lu, Joseph Polex-Wolf, Vincent Prevot, Kirsten Raun, Lotte Simonsen, Gao Sun, Anett Szilvásy-Szabó, Hanni Willenbrock, Anna Secher, Lotte Bjerre Knudsen

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Figure 5

GLP-1R neurons coexpress modulators of appetite regulation in areas directly targeted by peripheral administration of GLP-1RAs.

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GLP-1R neurons coexpress modulators of appetite regulation in areas dire...
(A−H) Representative immunofluorescence images taken from mouse ARH and AP processed for GLP-1R (green) and CART, SST, and TH, respectively (red). DAPI nuclear staining (blue). GLP-1R expression in (A−C) ARH, colocalized with CART, SST, and TH, respectively, and in (D) AP colocalized with TH. Dashed boxes indicate the location of the insets. (E−L) Confocal images from mice i.v. injected for 4 consecutive days with semaglutideCy3 (red) and DAPI nuclear stain (blue) applied. (E−H) Colocalization of semaglutideCy3 with GLP-1R in the ARH. Dashed box in E indicates location of F−H. (I−K) Colocalization of semaglutideCy3 with CART, SST, and TH, respectively, in the ARH and (L) with TH in AP. Scale bars: 100 μm (A−E), 10 μm (A−D insets and F−H), and 20 μm (L). SST, somatostatin.