Activation of bitter taste receptors regulates expression of growth differentiation factor 15 in the small intestine of patients with obesity
Mon-S1-003
Presented by: Qian Wang
Objectives
Bitter taste receptors (TAS2Rs, 25 subtypes) expressed on enteroendocrine cells regulate the release of gut hormones involved in appetite signaling. GDF15, a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the area postrema. This study aimed to investigate whether activation of TAS2Rs induces a stress response in gut epithelial cells to affect GDF15 expression in patients with obesity.
Methods
Jejunal mucosa was obtained from patients with obesity undergoing bariatric surgery. Primary crypts were isolated, cultured for 24h and stimulated with vehicle or bitter agonists for 4h followed by RT-qPCR for GDF15. Immunofluorescence colocalization studies were performed between GDF15 and TAS2R4/10/43. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV-3727; 2) determining TAS2R43 polymorphisms.
Results
TAS2R4/10/43 expressing cells colocalized with GDF15 immunoreactive cells in primary crypts from patients with obesity. The TAS2R4 agonists, gallic acid (1mM) and azithromycin (0.075-1mM), and the TAS2R10 agonist erythromycin (1mM) markedly increased (p<0.001) GDF15 mRNA expression in primary jejunal crypts from patients with obesity. GIV-3727 blocked the effect of gallic acid (p<0.001) but not of azithromycin on GDF15 mRNA expression. The TAS2R43 agonist aloin (0.03-0.1mM) decreased (p<0.001) GDF15 mRNA expression in patients who are more sensitive to aloin [TAS2R43(+)W35] but was ineffective in patients that were less sensitive [TAS2R43(+)S35] or that had a TAS2R43 deletion polymorphism. Bitter-induced GDF15 mRNA expression only resulted in a release of GDF15 after a secondary bitter stimulus.
Conclusions
TAS2Rs are involved in the effect of the bitter agonist gallic acid and aloin on GDF15 mRNA expression in patients with obesity. TAS2Rs in the gut may represent interesting therapeutic targets to affect satiety signaling via GDF15.
Funded by FWO G081523N; CSC202008370227
Bitter taste receptors (TAS2Rs, 25 subtypes) expressed on enteroendocrine cells regulate the release of gut hormones involved in appetite signaling. GDF15, a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the area postrema. This study aimed to investigate whether activation of TAS2Rs induces a stress response in gut epithelial cells to affect GDF15 expression in patients with obesity.
Methods
Jejunal mucosa was obtained from patients with obesity undergoing bariatric surgery. Primary crypts were isolated, cultured for 24h and stimulated with vehicle or bitter agonists for 4h followed by RT-qPCR for GDF15. Immunofluorescence colocalization studies were performed between GDF15 and TAS2R4/10/43. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV-3727; 2) determining TAS2R43 polymorphisms.
Results
TAS2R4/10/43 expressing cells colocalized with GDF15 immunoreactive cells in primary crypts from patients with obesity. The TAS2R4 agonists, gallic acid (1mM) and azithromycin (0.075-1mM), and the TAS2R10 agonist erythromycin (1mM) markedly increased (p<0.001) GDF15 mRNA expression in primary jejunal crypts from patients with obesity. GIV-3727 blocked the effect of gallic acid (p<0.001) but not of azithromycin on GDF15 mRNA expression. The TAS2R43 agonist aloin (0.03-0.1mM) decreased (p<0.001) GDF15 mRNA expression in patients who are more sensitive to aloin [TAS2R43(+)W35] but was ineffective in patients that were less sensitive [TAS2R43(+)S35] or that had a TAS2R43 deletion polymorphism. Bitter-induced GDF15 mRNA expression only resulted in a release of GDF15 after a secondary bitter stimulus.
Conclusions
TAS2Rs are involved in the effect of the bitter agonist gallic acid and aloin on GDF15 mRNA expression in patients with obesity. TAS2Rs in the gut may represent interesting therapeutic targets to affect satiety signaling via GDF15.
Funded by FWO G081523N; CSC202008370227