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Semaglutide lowers body weight in rodents via distributed neural pathways

Gabery, Sanaz LU ; Salinas, Casper G ; Paulsen, Sarah J ; Ahnfelt-Rønne, Jonas ; Alanentalo, Tomas ; Baquero, Arian F ; Buckley, Stephen T ; Farkas, Erzsébet ; Fekete, Csaba LU and Frederiksen, Klaus S , et al. (2020) In JCI Insight 5(6).
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
5
issue
6
article number
e133429
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85082831880
  • pmid:32213703
ISSN
2379-3708
DOI
10.1172/jci.insight.133429
language
English
LU publication?
no
id
632fda68-4293-45a7-8cb0-c3823e9a7b31
date added to LUP
2020-04-12 18:33:24
date last changed
2021-01-26 01:27:32
@article{632fda68-4293-45a7-8cb0-c3823e9a7b31,
  abstract     = {<p>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.</p>},
  author       = {Gabery, Sanaz and Salinas, Casper G and Paulsen, Sarah J and Ahnfelt-Rønne, Jonas and Alanentalo, Tomas and Baquero, Arian F and Buckley, Stephen T and Farkas, Erzsébet and Fekete, Csaba and Frederiksen, Klaus S and Helms, Hans Christian C and Jeppesen, Jacob F and John, Linu M and Pyke, Charles and Nøhr, Jane and Lu, Tess T and Polex-Wolf, Joseph and Prevot, Vincent and Raun, Kirsten and Simonsen, Lotte and Sun, Gao and Szilvásy-Szabó, Anett and Willenbrock, Hanni and Secher, Anna and Knudsen, Lotte Bjerre},
  issn         = {2379-3708},
  language     = {eng},
  month        = {03},
  number       = {6},
  publisher    = {The American Society for Clinical Investigation},
  series       = {JCI Insight},
  title        = {Semaglutide lowers body weight in rodents via distributed neural pathways},
  url          = {http://dx.doi.org/10.1172/jci.insight.133429},
  doi          = {10.1172/jci.insight.133429},
  volume       = {5},
  year         = {2020},
}