Current understanding and controversy on brain access of GLP-1 and GLP-1 receptor agonists

For more than two decades, peripheral administration of GLP-1 or GLP-1 receptor (GLP-1R) agonist (GLP-1RA) curbs appetite and reduce body weight gain in animal models. More importantly, the body weight lowering effect has been effectively observed in clinical practice. There is no doubt that the target sites for GLP-1 or GLP-1RAs to exert those functions are located in the brain. It, however, remains controversy on exactly how these drugs access their targets in the brain. Here, we have discussed literatures on whether peripheral GLP-1 or GLP-1RAs enters the brain via crossing the blood-brain barrier, or the blood cerebrospinal fluid barrier, or given circumventricular organs. We have then commented the view or opinion that peripheral GLP-1RAs may exert their brain functions via organ-organ communications without entering the brain.