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

Abstract

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.

• Authors: Anna Secher, Jacob Jelsing, Arian F Baquero, Jacob Hecksher-Sørensen, Michael A Cowley, Louise S Dalbøge, Gitte Hansen, Kevin L Grove, Charles Pyke, Kirsten Raun, Lauge Schäffer, Mads Tang-Christensen, Saurabh Verma, Brent M Witgen, Niels Vrang, Lotte Bjerre Knudsen
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 10 Pg. 4473-88 (Oct 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 25202980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glp1r protein, mouse
• Glp1r protein, rat
• Glucagon-Like Peptide-1 Receptor
• Nerve Tissue Proteins
• Receptors, Glucagon
• cocaine- and amphetamine-regulated transcript protein
• Pro-Opiomelanocortin
• Liraglutide
• Glucagon-Like Peptide 1

Topics

• Animals
• Arcuate Nucleus of Hypothalamus (drug effects)
• Body Weight (drug effects)
• Disease Models, Animal
• Electrophysiology
• Glucagon-Like Peptide 1 (analogs & derivatives, pharmacology)
• Glucagon-Like Peptide-1 Receptor
• Hypothalamus (metabolism)
• Liraglutide
• Male
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (metabolism)
• Neurons (metabolism)
• Paraventricular Hypothalamic Nucleus (metabolism)
• Pro-Opiomelanocortin (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glucagon (metabolism)
• Vagus Nerve (metabolism)
• Weight Loss (drug effects)