The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here,...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-10, Vol.124 (10), p.4473-4488
Main Authors: Secher, Anna, Jelsing, Jacob, Baquero, Arian F, Hecksher-Sørensen, Jacob, Cowley, Michael A, Dalbøge, Louise S, Hansen, Gitte, Grove, Kevin L, Pyke, Charles, Raun, Kirsten, Schäffer, Lauge, Tang-Christensen, Mads, Verma, Saurabh, Witgen, Brent M, Vrang, Niels, Bjerre Knudsen, Lotte
Format: Article
Language:English
Subjects:
Animals
Arcuate Nucleus of Hypothalamus - drug effects
Biomedical research
Body Weight - drug effects
Disease Models, Animal
Electrophysiology
Food
Glucagon-Like Peptide 1 - analogs & derivatives
Glucagon-Like Peptide 1 - pharmacology
Glucagon-Like Peptide-1 Receptor
Hypothalamus
Hypothalamus - metabolism
Liraglutide
Male
Medical examination
Mice
Mice, Transgenic
Nerve Tissue Proteins - metabolism
Neural circuitry
Neurons - metabolism
Obesity
Observations
Paraventricular Hypothalamic Nucleus - metabolism
Patient outcomes
Peptides
Physiological aspects
Physiology
Pro-Opiomelanocortin - metabolism
Rats
Rats, Sprague-Dawley
Receptors, Glucagon - metabolism
Rodents
Software
Vagus Nerve - metabolism
Weight control
Weight loss
Weight Loss - drug effects
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Summary:Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, 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, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). 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. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI75276