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 5

Distribution of liraglutide594 or exendin(9-39)594 in pancreas and brain.

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Distribution of liraglutide594 or exendin(9-39)594 in pancreas and brain...
(A–L) Representative images of mouse islets stained with Hoechst nuclear stain (blue), insulin (green), and liraglutide594/exendin(9-39)594 (red). (A–D) In C57BL/6J mice, both liraglutide594 and exendin(9-39)594 were detected in cells expressing insulin; (E–H) however, in mice lacking a functional GLP-1R, no liraglutide594 or exendin(9-39)594 signal could be detected in insulin expressing β cells. (I, J, and N) High-magnification images showed that liraglutide594 was internalized and the fluorescent signal was located in the cytoplasm, (K, L, and P) while exendin(9-39)594 remained at the plasma membrane. In the brain, (M and N) liraglutide594 had access to ARC, in which it bound the GLP-1R and internalized, (O and P) while exendin(9-39)594 labeled the same population of cells but without internalization. Scale bars: 100 μm (M and O), 50 μm (A–H), 10 μm (I–L, N, and P).