The mechanism of clinically used anti-obesity drugs targeting glucagon-like peptide 1 (GLP-1) receptor; an unexpected non-synaptic brain signalling
Description: Purpose and aim: We were first to publish evidence that endogenous interleukin-6 (IL-6) in the brain decreases fat mass, and that IL-6 mediates the suppression of food intake and body weight that is induced by glucagon-like peptide-1 (GLP-1) analogues. The aim is now to prove or disprove our hypothesis for the location of this effect. We believe that GLP-1 acts on GLP-1 receptors on IL-6 producing cells in the lateral hypothalamic area (LHA) and that these cells then project to IL-6 releasing nerve terminals close to the upper 3rd ventricle. IL-6 then exerts metabolic effects on its receptor (IL-6Rα) on tanycytes at some distance at the bottom of the 3rd ventricle.Implementation: In year 1 we will mainly map factors involved in the proposed chain of events, using multiple immunohistochemistry, RNAscope and a novel IL-6 reporter mouse. Thereafter, we will start to intervene with relevant molecules, cell types and brain areas. We will use viral vectors, chemogenetic (DREADD) techniques, CRE mediated gene depletion, and neutralizing antibodies.Importance: Unexpectedly, the present results are in line with the possibility that IL-6 reaches its receptors via the 3rd ventricle, reviving the hypothesis of non-synaptic signalling, “ventricular volume transmission”. Understanding the mechanism of action of successful obesity treatments like GLP-1 analogues is likely to result in new and more refined therapies.
Funder: Vetenskapsrådet
Amount: SEK 2,400,000
Funding type: research
Funder scheme: Project grant
Start date: 2020-01-01
End date: 2022-12-31
Investigator: John-Olov Jansson
Institution: University of Gothenburg
Funded outputs count: 4
Funder award ID: 2019-01164
OpenAlex ID: G2492926658