Diabetes and In Vivo Pharmacology, Merck Research Laboratories, Rahway, New Jersey, United States of America.
PLoS One. 2012;7(4):e35240. doi: 10.1371/journal.pone.0035240. Epub 2012 Apr 10.
Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.
短链脂肪酸（SCFAs）主要包括乙酸盐、丙酸盐和丁酸盐，是肠道微生物群从复杂的膳食碳水化合物中形成的代谢产物。有报道称，丁酸盐和乙酸盐可以预防饮食引起的肥胖，而不会导致食欲减退，而丙酸盐则可以减少食物摄入。然而，这些作用的潜在机制尚不清楚。有人提出，SCFAs 可能通过其内源性受体游离脂肪酸受体 2（FFAR2）和 3（FFAR3）来调节肠道激素，但缺乏直接证据。我们在小鼠中检查了 SCFA 给药的效果，结果表明丁酸盐、丙酸盐和乙酸盐均可预防饮食引起的肥胖和胰岛素抵抗。丁酸盐和丙酸盐会诱导肠道激素并减少食物摄入，但乙酸盐不会。由于 FFAR3 是丁酸盐和丙酸盐共同激活的受体，我们在 FFAR3 缺陷型小鼠中检查了这些效果。FFAR3 缺乏并不影响丁酸盐和丙酸盐对体重和食物摄入的影响。此外，FFAR3 在丁酸盐刺激胰高血糖素样肽-1（GLP-1）中的作用较小，并且对丁酸盐和丙酸盐依赖的葡萄糖依赖性胰岛素释放肽（GIP）的诱导也不是必需的。最后，FFAR3 缺陷型小鼠的体重和葡萄糖稳态正常。丁酸盐和丙酸盐刺激肠道激素和抑制食物摄入可能代表了肠道微生物群调节宿主代谢的一种新机制。这些作用在 FFAR3 缺陷型小鼠中基本完整，表明还需要其他介质来发挥这些有益作用。
