Fisetin Stimulates GLP-1 Secretion via Activation of TAS2Rs, and the Gα-gustducin-mediated Signaling Pathway
Diets rich in bitter vegetables are associated with a significant increase in longevity and wellness. Genetic variation in taste receptors, particularly the bitter taste-sensing type 2 receptors (Tas2rs), can modulate food preferences, and regulated food absorption and processing. Several studies have shown that Tas2rs are expressed in various extra-oral tissues, including the intestines, pancreas and adipose tissue. Given that bitter compounds can trigger the release of metabolic hormones such as glucagon-
like peptide 1 (GLP-1), we investigated whether the flavonoid Fisetin, identified as a senolytic compound that selectively induces apoptosis in senescent cells, signals through Tas2rs to stimulate GLP-1 secretion from intestinal cells. Our study demonstrated that Fisetin signals via Tas2r108, Tas2r135 and Tas2r121, three of the 35 murine Tas2Rs, in murine intestinal STC-1 cells. Treatment with low, non-toxic concentrations of Fisetin significantly increased GLP-1 secretion in the conditioned medium of STC-1 cells within one hour. Importantly, siRNA knockdown of Gα-gustducin, a primarily taste-specific G protein alpha-subunit, abolished this secretagogue effect. Additionally, pharmacologic inhibition of PLCβ2 and IP3R, which are known to participate in taste signal transduction, also partially alleviated the secretagogue effect of Fisetin. Overall, these results demonstrate that Fisetin mediated GLP-1 release in vitro via Tas2r signaling; however, the therapeutic translation to in vivo models requires further investigation.