Gut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
Mol Metab. 2024 Oct;88:102002. doi: 10.1016/j.molmet.2024.102002. Epub 2024 Aug 5.
Growth differentiation factor 15 (GDF15), a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the hindbrain. Bitter compounds are known to induce satiety via the release of glucagon-like peptide 1 (GLP-1) through activation of bitter taste receptors (TAS2Rs, 25 subtypes) on enteroendocrine cells in the gut. This study aimed to investigate whether and how bitter compounds induce a stress response in intestinal epithelial cells to affect GDF15 expression in patients with obesity, thereby facilitating satiety signaling from the gut.
The acute effect of oral intake of the bitter-containing medication Plaquenil (hydroxychloroquine sulfate) on plasma GDF15 levels was evaluated in a placebo-controlled, double-blind, randomized, two-visit crossover study in healthy volunteers. Primary crypts isolated from the jejunal mucosa from patients with obesity were stimulated with vehicle or bitter compounds, and the effect on GDF15 expression was evaluated using RT-qPCR or ELISA. Immunofluorescence colocalization studies were performed between GDF15, epithelial cell type markers and TAS2Rs. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV3727; 2) determining TAS2R4/43 polymorphisms that affect taste sensitivity to TAS2R4/43 agonists.
Acute intake of hydroxychloroquine sulfate increased GDF15 plasma levels, which correlated with reduced hunger scores and plasma ghrelin levels in healthy volunteers. This effect was mimicked in primary jejunal cultures from patients with obesity. GDF15 was expressed in enteroendocrine and goblet cells with higher expression levels in patients with obesity. Various bitter-tasting compounds (medicinal, plant extracts, bacterial) either increased or decreased GDF15 expression, with some also affecting GLP-1. The effect was mediated by specific intestinal TAS2R subtypes and the unfolded protein response pathway. The bitter-induced effect on GDF15/GLP-1 expression was influenced by the existence of TAS2R4 amino acid polymorphisms and TAS2R43 deletion polymorphisms that may predict patient's therapeutic responsiveness. However, the effect of the bitter-tasting antibiotic azithromycin on GDF15 release was mediated via the motilin receptor, possibly explaining some of its aversive side effects.
Bitter chemosensory and pharmacological receptors regulate the release of GDF15 from human gut epithelial cells and represent potential targets for modulating metabolic disorders or cachexia.
生长分化因子 15（GDF15）是一种与应激相关的细胞因子，最近被确定为一种新型饱食信号，通过位于后脑的 GFRAL 受体发挥作用。苦味化合物通过激活肠道内分泌细胞上的苦味受体（TAS2R，25 种亚型）释放胰高血糖素样肽 1（GLP-1）已知可诱导饱腹感。本研究旨在探讨苦味化合物是否以及如何诱导肥胖患者的肠道上皮细胞产生应激反应，从而影响 GDF15 的表达，从而促进来自肠道的饱食信号。
在健康志愿者的安慰剂对照、双盲、随机、两访交叉研究中，评估口服含苦味药物羟氯喹硫酸盐（hydroxychloroquine sulfate）对血浆 GDF15 水平的急性影响。从肥胖患者的空肠黏膜中分离出初级隐窝，用载体或苦味化合物刺激，并通过 RT-qPCR 或 ELISA 评估 GDF15 表达的影响。进行免疫荧光共定位研究，以确定 GDF15 与上皮细胞类型标志物和 TAS2R 之间的关系。通过以下方法测试 TAS2R 的作用：1）用 TAS2R 拮抗剂 GIV3727 预处理；2）确定影响 TAS2R4/43 激动剂味觉敏感性的 TAS2R4/43 多态性。
羟氯喹硫酸盐的急性摄入增加了 GDF15 的血浆水平，这与健康志愿者的饥饿评分降低和血浆 ghrelin 水平降低相关。这一作用在肥胖患者的原发性空肠培养中得到了模拟。GDF15 在肠内分泌细胞和杯状细胞中表达，在肥胖患者中表达水平更高。各种苦味化合物（药物、植物提取物、细菌）或增加或减少 GDF15 的表达，其中一些也影响 GLP-1。这种作用是由特定的肠道 TAS2R 亚型和未折叠蛋白反应途径介导的。苦味诱导的 GDF15/GLP-1 表达的影响受到 TAS2R4 氨基酸多态性和 TAS2R43 缺失多态性的影响，这些多态性可能预测患者的治疗反应性。然而，苦味抗生素阿奇霉素对 GDF15 释放的影响是通过胃动素受体介导的，这可能解释了其一些令人不快的副作用。
苦味化学感觉和药理学受体调节人肠道上皮细胞中 GDF15 的释放，代表了调节代谢紊乱或恶病质的潜在靶点。
