Identification of weight loss-mediating liraglutide targets
The type 2 diabetes drug liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers blood glucose and reduces body weight. Liraglutide is being investigated for clinical use as a treatment for obesity; however, the mechanism of action underlying the associated weight loss is not clear. In this episode, Lotte Bjerre Knudsen and colleagues reveal that liraglutide mediates weight loss via neurons in the arcuate nucleus. GLP-1R signaling activated centrally projecting neurons that express proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART neurons), which regulate appetite and are activated by leptin and insulin. Liraglutide also inhibited neuropeptide Y-expressing neurons, which enhance appetite. The results of this study provide important insight into how liraglutide mediates weight loss.
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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
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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ISSN: 0021-9738 (print), 1558-8238 (online)