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

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 Schäfer, Mads Tang-Christensen, Saurabh Verma, Brent M. Witgen, Niels Vrang, Lotte Bjerre Knudsen

    Research output: Contribution to journalArticle

    300 Scopus citations

    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 fuorescently 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.

    Original languageEnglish (US)
    Pages (from-to)4473-4488
    Number of pages16
    JournalJournal of Clinical Investigation
    Volume124
    Issue number10
    DOIs
    StatePublished - Oct 1 2014

    ASJC Scopus subject areas

    • Medicine(all)

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  • Cite this

    Secher, A., Jelsing, J., Baquero, A. F., Hecksher-Sørensen, J., Cowley, M. A., Dalbøge, L. S., Hansen, G., Grove, K. L., Pyke, C., Raun, K., Schäfer, L., Tang-Christensen, M., Verma, S., Witgen, B. M., Vrang, N., & Knudsen, L. B. (2014). The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Journal of Clinical Investigation, 124(10), 4473-4488. https://doi.org/10.1172/JCI75276