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 8

PVN and ARC contributions to liraglutide-induced body weight change.

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PVN and ARC contributions to liraglutide-induced body weight change. (A)...
(A) Exendin(9-39) led to a significant increase in body weight when administered into the PVN, whereas liraglutide treatment reduced body weight gain significantly alone and in combination with exendin(9-39) (*P < 0.001, vehicle PVN + liraglutide s.c. vs. vehicle PVN + vehicle s.c.; †P < 0.001, vehicle PVN + vehicle s.c. vs. exendin(9-39) PVN + liraglutide s.c.; #P < 0.001, exendin(9-39) PVN + vehicle s.c. vs. vehicle PVN + vehicle s.c.). (B) Exendin(9-39) led to a slight but nonsignificant increase in body weight when administered into the ARC, whereas the effect of liraglutide treatment was attenuated when administered in combination with exendin(9-39) (*P < 0.001, vehicle ARC + liraglutide s.c. vs. vehicle ARC + vehicle s.c.; †P < 0.001, vehicle ARC + vehicle s.c. vs. exendin(9-39) ARC + liraglutide s.c). (C) Lesion of the PVN led to a significant increase in body weight (#P < 0.001, PVN lesion + vehicle vs. sham + vehicle), whereas animals with PVN lesions were fully responsive to the weight loss induced by liraglutide (*P < 0.01, sham vehicle vs. sham liraglutide; †P < 0.001, PVN lesion + vehicle vs. PVN lesion + liraglutide). The PVN lesion was histologically verified in (D) sham and (E) PVN-lesioned rats. Data are mean ± SEM, and statistical analyses are performed using 2-way repeated-measures ANOVA, with Bonferroni post-hoc analyses applied. Scale bars: 500 μm.