Bitter substances in the human gut promote the expression of the stress-related hormone GDF15 to suppress food intake and body weight during obesity: an emerging target for combination therapy

Growth differentiation factor 15 (GDF15) is increased in response to cellular stress and reduces food intake and body weight by activating its receptor (GRFAL) in the hindbrain. GDF15 mediates the inhibitory effect of metformin, a bitter tasting type 2 diabetes medication, on body weight. Bitter substances in the gut decrease hunger scores in healthy volunteers and decrease body weight in obese mice by affecting the release of appetite regulating gut hormones (GLP-1, ghrelin). Our preliminary data show that bitter taste receptors and GDF15 colocalize in primary jejunal crypts of obese patients and that stimulation with bitter substances increases GDF15 expression. We hypothesize that the effects of bitter agonists on the release of GLP-1 and GDF15 may act additively to reduce food intake. This project will investigate in primary crypts from lean and obese patients, which and how bitter substances affect GDF15 and GLP-1 expression in the gut. In 3D enteroids, we will examine whether bitter agonists in the microenvironment of stems cells, can influence their fate during differentiation to the secretory lineage to increase the expression of GLP-1 and/or GDF15. The role of GDF15 in the effect of bitter substances on energy balance will be further elucidated in GRFAL-/- mice and in healthy volunteers. Our project will reveal whether bitterinduced GDF15 and GLP-1 release act as endocrine signals from the gut that can promote weight loss via distinct signalling pathways.