The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

被引：741

作者：

Secher, Anna ^{[1
]}

Jelsing, Jacob ^{[2
]}

Baquero, Arian F. ^{[3
]}

Hecksher-Sorensen, Jacob ^{[1
]}

Cowley, Michael A. ^{[4
]}

Dalboge, Louise S. ^{[2
]}

Hansen, Gitte ^{[2
]}

Grove, Kevin L. ^{[3
]}

Pyke, Charles ^{[1
]}

Raun, Kirsten ^{[1
]}

Schaffer, Lauge ^{[1
]}

Tang-Christensen, Mads ^{[1
]}

Verma, Saurabh ^{[3
]}

Witgen, Brent M. ^{[1
]}

Vrang, Niels ^{[2
]}

Knudsen, Lotte Bjerre ^{[1
]}

机构：

[1] Novo Nordisk AS, Diabet Res, DK-2760 Malov, Denmark

[2] Gubra Aps, Horsholm, Denmark

[3] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Diabet Obes & Metab, Beaverton, OR USA

[4] Monash Univ, Monash Obes & Diabet Inst, Clayton, Vic 3800, Australia

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2014年 / 124卷 / 10期

关键词：

GLUCAGON-LIKE PEPTIDE-1; FOOD-INTAKE; ENERGY-INTAKE; SUBFORNICAL ORGAN; BRAIN ACTIVATION; CHOROID-PLEXUS; AREA POSTREMA; BODY-WEIGHT; NEURONS; OBESE;

D O I：

10.1172/JCI75276

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：4473 / 4488

页数：16

共 95 条

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