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 October 1, 2014; First 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 2

Liraglutide treatment regulates ARC gene expression and ARC neuronal activity.

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Liraglutide treatment regulates ARC gene expression and ARC neuronal act...
(A) Liraglutide treatment for 28 days in DIO rats significantly increased mean Cart mRNA levels in the ARC (*P < 0.001 liraglutide vs. vehicle and vs. weight matched), whereas Pomc expression was unaffected. (B) Npy and Agrp mRNA levels were significantly increased in weight-matched rats — but not following treatment with liraglutide (#P < 0.05 weight matched vs. vehicle and vs. liraglutide). Data are mean ± SEM, and statistical analyses were performed using 1-way ANOVA, with Fishers post-hoc test. (C) Voltage-clamp recording of ARC-NPY neurons showed an increased outward current in the presence of GLP-1(7-36)amide (blue line) and an inward current with NMDA (red line). (D) Simultaneous GABA receptor inhibition by bicuculline (black line) showed a lack of change in the current with the addition of GLP-1(7-36)amide; however, NMDA retained the ability to cause an inward current. (E) The action of GLP-1(7-36) amide was not directly through GLP-1Rs on NPY/AgRP neurons, as no colocalization was observed between GLP-1R– (red, yellow arrows) and NPY/AgRP-positive (green, white arrows) neurons. Scale bars: 100 μm. (F) The effects of GLP-1(7-36)amide in the presence of bicuculline or NMDA on ARC-NPY neurons are summarized (mean ± SEM).