Piperine, as a TAS2R14 agonist, stimulates the secretion of glucagon-like peptide-1 in the human enteroendocrine cell line Caco-2

Dec 9, 2021Food & function

Piperine triggers release of a blood sugar-regulating hormone in human gut cells

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Abstract

Piperine significantly enhanced GLP-1 secretion in human enteroendocrine cells.

TAS2R14 was found to be highly expressed in Caco-2 cells compared to other bitter taste receptors.
Piperine and flufenamic acid increased intracellular calcium levels and boosted GLP-1 secretion.
The increase in GLP-1 secretion was associated with elevated proglucagon mRNA levels.
Piperine activated TAS2R14 signaling, leading to increased mRNA and protein levels of TAS2R14 and its downstream molecules, PLCβ2 and TRPM5.
Inhibition of G protein βγ subunit or phospholipase C reduced piperine-stimulated GLP-1 secretion.
Knockdown of TAS2R14 reversed the piperine-induced increases in PLCβ2, TRPM5, and GLP-1 secretion.

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Piperine is reported to ameliorate common metabolic diseases, however, its molecular mechanism is still unclear. In the present study, we examined whether piperine could stimulate glucagon-like peptide-1 (GLP-1) secretion in a human enteroendocrine cell line, Caco-2, and explored the potential mechanisms from the activation of human bitter taste receptors (TAS2Rs). It was found that TAS2R14 was highly expressed in Caco-2 cells, far more than TAS2R4 and TAS2R10. Piperine and flufenamic acid (FA, a known TAS2R14 agonist) markedly increased intracellular calcium mobilization and significantly enhanced the GLP-1 secretion, accompanied by elevated levels of proglucagon mRNA in Caco-2 cells compared with the control. Moreover, piperine and FA activated TAS2R14 signaling as evidenced by the increased mRNA and protein levels of TAS2R14, and the protein expression of its downstream key molecules including phospholipase C β2 (PLCβ2) and a transient receptor potential channel melastatin 5 (TRPM5). On the other hand, a G protein βγ subunit inhibitor Gallein or a PLC inhibitor U73122 alleviated piperine-stimulated GLP-1 secretion in Caco-2 cells. In the meantime, a flavanone hesperetin significantly attenuated piperine and FA induced the intracellular calcium mobilization and GLP-1 secretion. Furthermore, TAS2R14 knockdown reversed the piperine-triggered up-regulation of PLCβ2 and TRPM5 as well as increased the GLP-1 secretion in Caco-2 cells by TAS2R14 shRNA transfection. In summary, our findings demonstrated that piperine promoted the GLP-1 secretion from enteroendocrine cells through the activation of TAS2R14 signaling. Moreover, TAS2R14 was likely a target of piperine in the alleviation of metabolic diseases.

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Piperine, as a TAS2R14 agonist, stimulates the secretion of glucagon-like peptide-1 in the human enteroendocrine cell line Caco-2

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