The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon
The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon
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DOI：
10.1152/ajpgi.00346.2017
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发表时间：
2018-07-01
影响因子：
4.5
通讯作者：
Holst, Jens Juul
中科院分区：
文献类型：
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作者：
Christiansen, Charlotte Bayer;Gabe, Maria Buur Nordskov;Holst, Jens Juul
结肠上皮内含有大量的内分泌细胞，但对结肠的内分泌功能知之甚少。然而，高密度的胰高血糖素样肽-I（GLP-1）-和肽-YY（PYY）-分泌L细胞是非常令人感兴趣的，因为GLP-1和PYY的潜在抗糖尿病和抗肥胖作用。由局部细菌发酵产生的短链脂肪酸（SCFA）被认为激活结肠游离脂肪酸受体FFAR 2（GPR 43）和FFAR 3（GPR 41），刺激结肠L细胞。我们使用离体灌流大鼠结肠作为结肠内分泌的模型，并研究了主要SCFAs形成的影响：乙酸，丙酸和丁酸。我们发现，腔，特别是血管输注乙酸和丁酸显着增加结肠GLP-1分泌，并在较小程度上也PYY分泌，但只有在增强细胞内cAMP。丙酸盐既不影响GLP-1也不影响PYY分泌，无论是腔内给药还是血管给药。FFAR 2和FFAR 3特异性激动剂[（S）-2-（4-氯苯基）-3，3-二甲基-N（5-苯基噻唑-2-基）丁酰胺（CFMB）/AR 420626]对结肠GLP-1输出无影响，FFAR 3拮抗剂（AR 399519）未降低SCFA诱导的GLP-1反应。然而，电压门控性钙通道阻滞剂硝苯地平，K-ATP通道开放剂二氮嗪，ATP合成抑制剂2，4-二硝基苯酚完全取消的反应。FFAR 2受体研究证实了与CLIMB相比，乙酸盐、丙酸盐和丁酸盐的低效部分激动作用，CLIMB是一种完全激动剂，效力比SCFA高750倍。总之。SCFA可能增加结肠GLP-1/PYY分泌，但FFAR 2/FFAR 3似乎不参与。相反，SCFAs的代谢，似乎作为一个colonocyte能源。新&值得注意的是通过使用原位分离灌注大鼠结肠，我们表明，短链脂肪酸（SCFAs）主要是作为一个colonocyte能源在大鼠。随后不依赖于游离脂肪酸受体FFAR 2和FFAR 3而触发胰高血糖素样肽-1（GLP-1）分泌。与许多先前关于SCFA和FFAR 2/FFAR 3和GLP-1分泌的研究相反，该实验模型允许研究腔营养物与细胞分泌物之间的生理相互作用，这些细胞的功能严重依赖于其血液供应以及神经和旁分泌相互作用。
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 Ca2+-channel blocker nifedipine, the K-ATp-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 CLIMB, which is a full agonist with similar to 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.