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.
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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

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Figure 6

Neuronal accumulation and activity following GLP-1R stimulation.

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Neuronal accumulation and activity following GLP-1R stimulation. (A–C) H...
(A–C) Hypothalamic sections from rats injected with liraglutide594 (red) and stained with Hoechst nuclear stain (blue) and CART (green). (B and C) High-magnification confocal images revealed accumulation of fluoro liraglutide in the cytoplasm of CART-positive cells (arrows). (B) CART- and liraglutide594-positive cells. (C) The same image as in B with only liraglutide594 signal. (D) Double in situ hybridization/immunohistochemistry staining revealed that GLP-1R (red) colocalize (yellow arrows) with POMC/CART (green) in the ARC. (E) GLP-1 (10 nM and 100 nM) caused membrane depolarization and increased firing rate of spontaneous action potentials in POMC/CART cells. Dashed line indicates the resting membrane potential (RMP). The effects of increased concentrations of GLP-1(7-36)amide are summarized in F. (G) The effects of GLP-1(7-36)amide on firing rate of spontaneous action potentials in POMC/CART neurons. Results are shown as mean ± SEM. Scale bars: 25 μm (B and C); 100 μm (A and D). **P < 0.01 one-way ANOVA, post-hoc Bonferroni’s correction.