Martchenko Alexandre, Biancolin Andrew D, Martchenko Sarah E, Brubaker Patricia L
Department of Physiology, University of Toronto, Rm 3366 Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Department of Medicine, University of Toronto, Toronto, ON, Canada.
Sci Rep. 2022 May 4;12(1):7271. doi: 10.1038/s41598-022-11223-7.
The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted by the intestinal L cell in response to nutrient intake. However, GLP-1 secretion also follows a circadian rhythm which is disrupted by the saturated fatty acid palmitate in vitro and high-fat diet (HFD) feeding in vivo. The flavonoid nobiletin is a clock enhancer which improves metabolic homeostasis. Therefore, the aim of this study was to elucidate whether and how nobiletin mitigates the negative effects of palmitate and HFD-feeding on rhythmic GLP-1 release. Pre-treatment of murine GLUTag L cells with palmitate dampened the GLP-1 secretory response at the normal peak of secretion, while nobiletin co-treatment restored GLP-1 secretion and upregulated the 'metabolic pathway' transcriptome. Mice fed a HFD also lost their GLP-1 secretory rhythm in association with markedly increased GLP-1 levels and upregulation of L cell transcriptional pathways related to 'sensing' and 'transducing' cellular stimuli at the normal peak of GLP-1 release. Nobiletin co-administration reduced GLP-1 levels to more physiological levels and upregulated L cell 'oxidative metabolism' transcriptional pathways. Furthermore, nobiletin improved colonic microbial 16S rRNA gene diversity and reduced the levels of Proteobacteria in HFD-fed mice. Collectively, this study establishes that nobiletin improves the normal rhythm in GLP-1 secretion following fat-induced disruption.
肠促胰岛素激素胰高血糖素样肽-1（GLP-1）由肠道L细胞分泌，以响应营养物质的摄入。然而，GLP-1的分泌也遵循昼夜节律，在体外，饱和脂肪酸棕榈酸酯以及在体内高脂饮食（HFD）会破坏这种节律。类黄酮诺必亭是一种生物钟增强剂，可改善代谢稳态。因此，本研究的目的是阐明诺必亭是否以及如何减轻棕榈酸酯和高脂饮食对GLP-1节律性释放的负面影响。用棕榈酸酯预处理小鼠GLUTag L细胞会减弱分泌正常峰值时的GLP-1分泌反应，而诺必亭联合处理可恢复GLP-1分泌并上调“代谢途径”转录组。喂食高脂饮食的小鼠在GLP-1释放正常峰值时，其GLP-1分泌节律也会丧失，同时GLP-1水平显著升高，与L细胞中与“感知”和“转导”细胞刺激相关的转录途径上调有关。联合使用诺必亭可将GLP-1水平降低至更接近生理水平，并上调L细胞的“氧化代谢”转录途径。此外，诺必亭改善了高脂饮食喂养小鼠的结肠微生物16S rRNA基因多样性，并降低了变形菌门的水平。总的来说，本研究证实诺必亭可改善脂肪诱导破坏后GLP-1分泌的正常节律。
