Submit a comment

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss
Anna Secher, … , Niels Vrang, Lotte Bjerre Knudsen
Anna Secher, … , Niels Vrang, Lotte Bjerre Knudsen
Published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4473-4488. https://doi.org/10.1172/JCI75276.
View: Text | PDF
Research Article

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

×

Guidelines

The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.

  • Comments appear on the Journal’s website and are linked from the original article’s web page.
  • Authors are notified by email if their comments are posted.
  • The Journal reserves the right to edit comments for length and clarity.
  • No appeals will be considered.
  • Comments are not indexed in PubMed.

Specific requirements

  • Maximum length, 400 words
  • Entered as plain text or HTML
  • Author’s name and email address, to be posted with the comment
  • Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
  • Comments may not include figures
This field is required
This field is required
This field is required
This field is required
This field is required
This field is required