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 1

Vagal and AP contributions to liraglutide body weight change.

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Vagal and AP contributions to liraglutide body weight change. (A) Liragl...
(A) Liraglutide treatment reduced body weight gain significantly in both sham and SDA rats (*P < 0.001 sham vehicle vs. sham liraglutide; #P < 0.001 SDA vehicle vs. SDA liraglutide). (B) Whereas AP lesion changed the body weight set point, liraglutide treatment reduced body weight gain to the same degree in both sham and AP-ablated animals (*P < 0.001 sham vehicle vs. sham liraglutide; #P < 0.001 APx vehicle vs. APx liraglutide). (C and D) Wheat germ agglutinin (WGA) injected into the left nodose ganglion labeled afferent fibers in sham animals only (arrows). Note persistence of retrograde labeled dorsal motor nucleus neurons in both groups (double arrows). (E and F) Ablation of AP was verified histologically in (E) sham and (F) AP-ablated rats. Data are mean ± SEM, and statistical analyses are performed using 2-way repeated-measures ANOVA, with Bonferroni post-hoc analyses applied. (G and H) Efferent labeling of fluorogold injected i.p. was reduced in the gastrointestinal part of dorsal motor nucleus due to right truncal vagotomy (arrows). (I) CCK8 (8 μg/kg i.p.) reduced 30-minute food intake in sham rats but not in SDA-operated rats (*P < 0.01). Scale bars: 200 μm (C and D), 500 μm (E–H).