Bitter substances in the gut increase the stress-related hormone GDF15 in addition to GLP-1, to affect food intake and body weight during obesity

Growth differentiation factor 15 (GDF15) reduces food intake and body weight by activating its receptor (GRFAL) in the hindbrain. GDF15 mediates the inhibitory effect of metformin, a type 2 diabetes medication, on body weight. Metformin is a bitter tasting compound and intra-gastric administration of a bitter substance is known to decrease hunger signaling in healthy volunteers and to decrease body weight in obese mice by affecting the release of appetite regulating gut hormones (ghrelin, GLP-1). Our preliminary data show that bitter compounds in primary jejunal crypts of obese patients induce a stress response and increase GDF15 expression. We hypothesize that the effects of bitter agonists on the release of GLP-1 and GDF15, that act in two different brain regions, may act additively to induce anorectic signaling. This project will investigate in 3D enteroids from lean and obese patients, which and how bitter substances affect GDF15 and GLP-1 expression in the gut. We will study whether bitter, directly or indirectly via GDF15, affects epithelial lineage commitment of stem cells to compensate for the loss in enteroendocrine cells during obesity. The role of GDF15 in the effect of bitter compounds on energy balance will be further elucidated in GRFAL-/-mice and in healthy volunteers. Our project will reveal whether GDF15 and GLP-1 increase in response to bitter agonists and act as endocrine signals from the gut that can additively promote weight loss.