Liraglutide Weight Loss Study
Objective: Determine that liraglutide-dependent body weight reduction in rats is mediated by GLP-1 receptors in the arcuate nucleus and characterize the neural mechanisms independent of vagal pathways and other brain regions
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Equipment1
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Materials2
Software1
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Protocol Steps
Peripheral injection of fluorescently labeled liraglutide
Administer fluorescently labeled liraglutide via peripheral injection to mice to track drug distribution
Note: Used to reveal presence of drug in circumventricular organs
View evidence from paper
“Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs”
Assess liraglutide binding in brain tissue
Examine labeled liraglutide binding to neurons within the arcuate nucleus and other discrete sites in the hypothalamus
Note: Binding was not observed in Glp1r−/− mice, indicating GLP-1R requirement for liraglutide uptake
View evidence from paper
“Labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain”
Characterize liraglutide internalization in ARC neurons
Determine that liraglutide is internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)
Note: Specific neuronal populations identified in the arcuate nucleus
View evidence from paper
“In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)”
Perform electrophysiological measurements on brain slices
Conduct electrophysiological recordings on murine brain slices to measure direct and indirect effects of GLP-1 on neuronal populations
Note: Measurements reveal GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits NPY/AgRP neurons via GABA-dependent signaling
View evidence from paper
“Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling”
Assess body weight reduction in liraglutide-treated rats
Measure liraglutide-dependent body weight reduction in rats and determine independence from GLP-1 receptors in vagus nerve, area postrema, and paraventricular nucleus
Note: Weight loss is independent of GLP-1Rs in vagal pathways and specific brain regions tested
View evidence from paper
“Liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus”