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.