Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Copenhagen , Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.
Am J Physiol Gastrointest Liver Physiol. 2018 Jul 1;315(1):G53-G65. doi: 10.1152/ajpgi.00346.2017. Epub 2018 Mar 1.
The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of glucagon like peptide-1 (GLP-1)- and peptide-YY (PYY)-secreting L cells is of great interest because of the potential antidiabetic and antiobesity effects of GLP-1 and PYY. Short-chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects of the predominant SCFAs formed: acetate, propionate, and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP-1 nor PYY secretion whether administered luminally or vascularly. A FFAR2- and FFAR3-specific agonist [( S)-2-(4-chlorophenyl)-3,3-dimethyl- N-(5-phenylthiazol-2-yl)butamide (CFMB)/ AR420626 ] had no effect on colonic GLP-1 output, and a FFAR3 antagonist ( AR399519 ) did not decrease the SCFA-induced GLP-1 response. However, the voltage-gated Ca-channel blocker nifedipine, the K-channel opener diazoxide, and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate, and butyrate, compared with CFMB, which is a full agonist with ~750-fold higher potency than the SCFAs. In conclusion, SCFAs may increase colonic GLP-1/PYY secretion, but FFAR2/FFAR3 do not seem to be involved. Rather, SCFAs are metabolized and appear to function as a colonocyte energy source. NEW & NOTEWORTHY By the use of in situ isolated perfused rat colon we show that short-chain fatty acids (SCFAs) primarily are used as a colonocyte energy source in the rat, subsequently triggering glucagon like peptide-1 (GLP-1) secretion independent of the free fatty acid receptors FFAR2 and FFAR3. Opposite many previous studies on SCFAs and FFAR2/FFAR3 and GLP-1 secretion, this experimental model allows investigation of the physiological interactions between luminal nutrients and secretion from cells whose function depend critically on their blood supply as well as nerve and paracrine interactions.
结肠上皮含有大量内分泌细胞，但人们对结肠的内分泌功能知之甚少。然而，高浓度的胰高血糖素样肽-1（GLP-1）和肽 YY（PYY）分泌 L 细胞引起了极大的兴趣，因为 GLP-1 和 PYY 具有潜在的抗糖尿病和抗肥胖作用。局部细菌发酵产生的短链脂肪酸（SCFAs）被认为可以激活结肠游离脂肪酸受体 FFAR2（GPR43）和 FFAR3（GPR41），刺激结肠 L 细胞。我们使用分离的灌注大鼠结肠作为结肠内分泌分泌模型，研究了主要形成的 SCFAs 的影响：乙酸盐、丙酸盐和丁酸盐。我们发现，腔内和特别是血管内输注乙酸盐和丁酸盐可显著增加结肠 GLP-1 的分泌，并且在较小程度上也增加 PYY 的分泌，但仅在细胞内 cAMP 增强后才发生。无论是腔内还是血管内给予丙酸盐，都不会影响 GLP-1 或 PYY 的分泌。FFAR2 和 FFAR3 特异性激动剂[（S）-2-（4-氯苯基）-3,3-二甲基-N-（5-噻唑-2-基）丁酰胺（CFMB）/AR420626]对结肠 GLP-1 输出没有影响，FFAR3 拮抗剂（AR399519）也没有降低 SCFA 诱导的 GLP-1 反应。然而，电压门控钙通道阻滞剂硝苯地平、钾通道开放剂二氮嗪和 ATP 合成抑制剂 2,4-二硝基苯酚完全消除了这些反应。FFAR2 受体研究证实，与 CFMB 相比，乙酸盐、丙酸盐和丁酸盐具有低效力的部分激动作用，CFMB 是一种完全激动剂，其效力比 SCFAs 高约 750 倍。总之，SCFAs 可能会增加结肠 GLP-1/PYY 的分泌，但 FFAR2/FFAR3 似乎并未参与其中。相反，SCFAs 被代谢并似乎作为结肠细胞的能量来源。新内容和值得注意的内容通过使用原位分离灌注大鼠结肠，我们表明短链脂肪酸（SCFAs）主要在大鼠中用作结肠细胞的能量来源，随后触发胰高血糖素样肽-1（GLP-1）的分泌，而不依赖于游离脂肪酸受体 FFAR2 和 FFAR3。与许多关于 SCFAs 和 FFAR2/FFAR3 与 GLP-1 分泌的先前研究相反，这种实验模型允许研究腔内容物与依赖其血液供应的细胞分泌之间的生理相互作用，以及神经和旁分泌相互作用。
