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

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.

Recent evidence links 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 large bowel. Previous studies show that increasing the NDC in the diet reduces appetite and body weight and increase insulin sensitivity. Unfortunately, the high doses required to produce these effects are unpalatable and result in gastrointestinal side effects. 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. These effects of NDCs on appetite and insulin sensitivity are thought to be mediated via the production of the short chain fatty acid (SCFA) propionate which acts via the recently identified G protein coupled receptor GPR43. Proprionate acts on the GPR43 in enteroendocrine cells in the colon to stimulate the release of the anorexic gut hormones PYY and GLP-1., and on GPR43 in adipocytes to reduce free fatty acid output. Reducing circulating free fatty acid levels increases insulin sensitivity. Thus increasing colonic and systemic concentrations of propionate offers a potential therapy for the current obesity epidemic. To predictably increase colonic propionate release we have developed a novel system to deliver known amounts of propionate to the colon. We will test the hypothesis that elevated concentrations of colonic and systemic propionate will lead to a decrease in body weight through stimulation of appetite regulatory gut hormones and insulin sensitivity through suppression of free fatty acids. This study will determine the effect of 24 weeks diet supplementation with this propionate ester molecule on appetite, body weight and insulin sensitivity in obese volunteers. In collaboration with Leatherhead Food International and Premier Foods we will design foods which can be used to supplement the diet of the general population with propionate ester.

Impact on researchers The proposal will determine if chronic increases in colonic propionate reduce appetite and body weight and improve insulin sensitivity. It will also demonstrate proof of principle for using an non-digestible carbohydrate (NDC) ester to deliver a specific short chain fatty acid (SCFA) to the large intestine. This project will therefore provide valuable information for future studies investigating the effects of SCFAs on biological systems. If this project products positive results then this will be a major step forward for nutritional science. We will also complete the preliminary work necessary to translate the results into a public health initiative. The multidisciplinary nature of this research demonstrates the applicability to other disciplines. The research cuts across nutrition, food science, chemistry, physiology, medicine and public health. Determining that increasing colonic propionate reduces appetite and body weight may stimulate other scientists to investigate other ways of increasing colonic propionate, and to use this SCFA ester delivery system to investigate the effects of SCFAs on other biological systems. Policy makers and Public sector: If the project is successful then this will be a major public health step forward. The partnership with industry and the product development mean that a large percentage of the population could gain benefit from increase in colonic propionate. Impact on the population: A recent review by the Government's Foresight group concluded that most adults in the UK are already overweight and predicted that by 2050 60% of men and 50% of women in the UK will be clinically obese. The major beneficiary of this work will be the overweight and obese population. A decrease in body weight in the overweight is associated with improvement in quality on life, less sick days and better overall performance. Impact on the nation's wealth: If the trials prove positive and the product translated into the market place the potential to have a positive effect on human health is enormous. The impact on limiting weight gain in the lean and decreasing weight in the obese will have large financial benefit for the health system through savings made in obesity related ill health. Obesity is associated with increased risk of many diseases, including diabetes, cardiovascular disease and certain cancers. Obesity is directly related to increased mortality, causing 600 premature deaths in the UK per week. Without action, by 2050 obesity-related diseases are predicted to cost the UK National Health Service (NHS) £6 billion per year. Thus any intervention capable of reducing this burden would also have significant economic benefits for the NHS and UK Industrial Impact: This work will also provide data of major benefit to the food industry. Few NDCs have been shown to have a significant or specific impact on propionate production. In this proposal we intend to use a propionate ester to deliver high levels of propionate to the large bowel. Should this work demonstrate the efficacy of propionate on appetite regulation, body composition and insulin sensitivity this could lead to the development of foods designed to increase propionate in the large bowel in ways acceptable to the consumer. Give the worldwide epidemic of obesity and given the evidence that this study will provide it would make it commercially viable to product aimed at increasing colonic propionate as a tool to decrease body weight and potentially could increase success of industry.