Increased Propionate Production In The Colon Is Associated With Reduced Appetite Body Weight And Improved Insulin Sensitivity

肥胖是大多数发达国家和许多发展中国家面临的最大公共卫生挑战。肥胖与死亡率增加直接相关，在英国每周导致600人过早死亡。在目前肥胖流行的情况下，对工业合作伙伴来说，使用治疗性食品来解决肥胖问题可能在经济上是可行的。最近的流行病学和实验研究将非消化碳水化合物（NDC）消费的减少与肥胖的增加联系起来。ndc在小肠中不会被分解，但可以在大肠的一部分结肠中被细菌发酵。先前的研究和我们自己的试点数据表明，增加动物和人类饮食中的NDC会降低食欲和体重，并增加胰岛素敏感性。不幸的是，产生这些效果所需的高剂量是令人不快的，并导致副作用，限制了NDC补充剂作为肥胖或糖尿病治疗的使用。短链脂肪酸（SCFA）是NDC在结肠中发酵产生的分子，负责NDC的生物学效应。最近，发现了一种结合SCFA，特别是丙酸SCFA的受体。这种受体存在于大肠细胞中，刺激食欲抑制激素的释放，也存在于脂肪细胞中，减少游离脂肪酸的释放。减少体内游离脂肪酸的水平会增加身体对胰岛素的敏感性，从而减少2型糖尿病中存在的胰岛素抵抗的影响。到目前为止，控制结肠中丙酸的产生是不可能的。摄入的NDC类型和个体的肠道微生物群决定了结肠中产生的短链脂肪酸的水平和类型。最近，我们开发了一种新的分子，其中丙酸盐与载体分子结合。将本体酸与其载体分子连接起来的化学键在肠道的大多数部位都不能被分解。然而，在结肠中，这种化学键被存在的细菌破坏，将一定量的丙酸盐输送到结肠中。我们已经证明，与对照组相比，在老鼠的饮食中补充这种本体酸载体分子可以减轻它们的体重，而在人类中，它可以减少饥饿感和食物摄入量。本研究将确定24周饮食补充丙酸载体分子对肥胖志愿者食欲、体重和胰岛素敏感性的影响。我们将验证在日粮中添加丙酸载体分子会通过肠道激素释放降低食欲，并通过降低循环中游离脂肪酸浓度提高胰岛素敏感性的假设。工业界将在开发在结肠中产生丙酸以降低食欲和改善胰岛素敏感性的产品方面发挥重要作用。在与Leatherhead Food International的合作下，我们将设计出一种食品，可以用本体载体来补充普通人群的饮食。鉴于目前肥胖率的趋势，证明结肠丙酸生成和食欲调节之间的联系对公共卫生具有重要意义。然而，如果丙酸的结肠产量增加饱腹感，那么简单地添加任何NDC可能不足以将丙酸产量增加到显著水平，从而影响饱腹感。本研究将确定结肠丙酸是否会导致食欲和体重下降，并引起有益的代谢变化，并将证明使用NDC酯将scfa输送到大肠的原理。因此，这些数据将为未来研究SCFAs对食欲调节和胰岛素敏感性的影响提供有价值的信息。工业界将在开发在结肠中产生丙酸以降低食欲和改善胰岛素敏感性的产品方面发挥重要作用。

Obesity is the greatest public health challenge facing most developed and many developing countries. Obesity is directly related to increased mortality, causing 600 premature deaths in the UK per week. In the current obesity epidemic, using therapeutic foodstuff to tackle obesity is potentially a would be economically viable for industrial partners. Recent epidemiological and experimental studies link the decline in consumption of non digestible carbohydrates (NDC) to the rise in obesity. NDCs are not broken down in the small intestine, but can be fermented by bacteria in the colon, part of the large intestine. Previous studies and our own pilot data shows that increasing the NDC in the diet of animals and humans reduces appetite and body weight and increase insulin sensitivity. Unfortunately, the high doses required to produce these effects are unpalatable and result in side effects, limiting the use of NDC supplements as a treatment for obesity or diabetes. Short chain fatty acids (SCFA) are molecules produced by the fermentation of NDC in the colon and are responsible for the biological effects of NDC. Recently, a receptor has been found that binds SCFAs, and in particular the SCFA propionate. This receptor is found on cells in the large bowel where it stimulates the release appetite-inhibiting hormones, and on fat cells where it acts to decrease the release of free fatty acids. Reducing free fatty acid levels within the body increases the sensitivity of the body to insulin and thus reduces the effect of insulin resistance which is present in type 2 diabetes. Until now, controlling the production of propionate in the colon has been impossible. Both the type of NDC ingested and the gut microbiota of an individual dictate the levels and types of SCFA produced in the colon. Recently, we have developed a novel molecule in which propionate is bound to a carrier molecule. The chemical bond that links proprionate to its carrier molecule cannot be broken down in most parts of the gut. However, in the colon, this chemical bond is broken by the bacteria present there, delivering specific amounts of propionate to the colon. We have shown that supplementing the diet of rats with this proprionate carrier molecule reduces their body weight compared to controls, and that in humans it reduces hunger and food intake. This study will determine the effect of 24 weeks diet supplementation with this propionate carrier molecule on appetite, body weight and insulin sensitivity in obese volunteers. We will test the hypothesis that supplementing the diet with propionate carrier molecule will reduce appetite through gut hormone release and improve insulin sensitivity by reducing the concentration of free fatty acids in circulation. Industry will have an important role in developing products which produce propionate in the colon to reduce appetite and improve insulin sensitivity. In collaboration with Leatherhead Food International we will design foods which can be used to supplement the diet of the general population with proprionate carrier. Demonstrating the link between colonic propionate production and appetite regulation has significant implications for public health given current trends in obesity rates. However, if colonic production of propionate increases satiety, then simply adding any NDC may not be sufficient to increase propionate production to a significant level to impact on satiety. This study will determine if colonic propionate leads to a reduction in appetite and body weight and cause beneficial metabolic change, and will demonstrate proof of principle for using NDC esters to deliver SCFAs to the large intestine. These data will therefore provide valuable information for future studies investigating the effects of SCFAs on appetite regulation and insulin sensitivity. Industry will play an important role in developing products which produce propionate in the colon to reduce appetite and improve insulin sensitivity.