The effect of fructose on human hepatocyte-adipocyte cellular crosstalk and metabolic health

People are often confused about the sugars in their diet and ask questions such as:
Isn't fructose a fruit sugar? If fructose is so bad for me should I be eating less fruit? I've been told soft drinks and sweets are bad for me, why is this?

Fructose is the major fruit sugar; however it has unfavourable effects on health when consumed in excess through the consumption of products rich in 'added' sugars such as sweets and soft-drinks, rather than consumption of fruit. As the consumption of these products has increased over time, it has been suggested that added fructose in those products may directly contribute to the growing rates of obesity and obesity-related diseases such as type 2 diabetes and heart disease. As humans typically consume fructose in combination with glucose; we would like to understand how these sugars affect the function of two organs in the human body which play important roles in maintaining our health; adipose tissue and the liver. We would like to understand how adipose tissue and liver process fructose and whether elevated levels of fructose cause changes in function of the individual cells that make up these organs. We are able to investigate both aspects, firstly, by doing studies in healthy human participants and secondly, by using cells grown in the laboratory that have been donated by human volunteers.

To understand whether having too much sugary food in our diets affects our health as a result of changes in normal adipose tissue and liver function we will study healthy people before and after they have altered their diet to include more foods that contain large amounts of fructose with glucose (e.g. soft-drinks). To determine the effect of having too much sugary food on adipose tissue and liver metabolism we will use specially labelled molecules (stable-isotopes), which have the equivalent of a GPS (global positioning signal) tag attached. The stable-isotopes will be eaten as part of a test meal and infused directly into the bloodstream of the participants. By taking regular blood samples over the course of the study day, we can then use techniques to detect the "GPS" signal in the blood to determine if adipose tissue and liver function have been changed by the sugary diet. We will use a specialised technique (called arterio-venous difference) to study adipose tissue on the human body that is on the tummy (abdominal) and on the upper leg/buttock (gluteofemoral). We will study these two fat depots as there is evidence to suggest fat from these sites has different functions and can have opposite effects on human health.

To look in closer detail at the pathways involved in processing fructose and changes in cell function caused by fructose we will isolate individual cells from human adipose tissue (called preadipocytes) and human liver (called hepatocytes). The cells will be exposed to varying amounts of fructose and glucose and we will measure changes in the health and function of the cells. In addition to using stable-isotopes to trace the metabolism of fructose and glucose, we can also look at markers of cell death, the ability of the cells to make and store fat, the production of energy and whether normal signalling pathways are disrupted. We will also measure signals released by the adipocytes and hepatocytes when they are exposed to fructose; identifying these signals will provide further information of cell function. We will then investigate whether these signals are used as a form of communication between the adipose tissue and liver.

These studies are important because, at present, there is much confusion surrounding the effects sugary foods have on human health. Our studies will provide important answers to how fructose is processed in the human body and what effects elevated fructose consumption has on human health. We hope that our findings will be used to provide information toward nutritional advice to reduce the risk of developing obesity and obesity-associated diseases.

The proposed work aims to use an in vivo human dietary intervention study and in vitro human cellular models to test the hypothesis that fructose, when given with glucose, modifies metabolic and molecular cellular processes in adipose tissue and liver and, as a result, disturbs healthy-state cross-talk between these two tissues.

To understand the effects of dietary fructose at a whole-body and tissue-specific level, we will undertake a short-term dietary intervention in healthy subjects and study them before and after the 'overconsumption' of free sugars. Subjects will undergo a postprandial study day at baseline and end of the study to assess in vivo adipose tissue function; stable-isotope tracers and arterio-venous difference methodologies will be utilised. By including stable-isotope tracers we will also be able to simultaneously determine the effect of the intervention on liver metabolism.

To investigate the metabolic and molecular processes influenced by fructose we will isolate primary human preadipocytes from subcutaneous adipose tissue, and hepatocytes from human liver, for in vitro cell studies. Both cell types will be cultured in the presence of varying concentrations of fructose and glucose. Stable isotope tracers will be added and isotope enrichment into intermediary and end product metabolites measured. Effects of fructose on adipocyte and hepatocyte function will be determined using molecular techniques to assess viability, insulin sensitivity, fatty acid synthesis, cellular respiration and the inflammatory response.

This will be one of the first studies to simultaneously assess the effects of the fructose component of free sugars using human in vivo and in vitro cellular models, for two specific tissues. The findings will aid in underpinning future nutritional guidelines that may play a role in preventing and treating metabolic diseases such as type 2 diabetes and cardiovascular disease.

This proposal will further understanding of how dietary sugars impact on adipose tissue and liver metabolism, providing much needed evidence in an emerging area of concern. There are strong positive associations between the consumption of free (added/non-milk extrinsic) sugars and risk of obesity or increased adiposity. Moreover, the consumption of sugar-sweetened beverages has been strongly associated with increased risk of non-communicable diseases such as type 2 diabetes, cardiovascular disease (CVD) and liver disease. The British Heart Foundation has reported that CVD is responsible for over a quarter of the deaths in the UK and it is estimated 7 million people are living with CVD in the UK. The financial burden to the UK of premature death, lost productivity, hospital treatment and prescriptions relating to CVD is estimated at £19 billion each year. Although not mentioned as often, liver disease, specifically non-alcoholic fatty liver disease (NAFLD) is also of great concern. The British Liver Trust states that liver disease is the only major cause of death that is still increasing year-on-year and is the fifth 'big killer' in England & Wales, after heart disease, cancer, stroke and respiratory disease. This increasing prevalence is having not only a huge impact on the lives of sufferers, but also results in a substantial cost to the National Health Service. In 2011, the direct healthcare costs of liver disease were estimated to be in excess of £0.5bn per annum.

The present study addresses the impact of free sugar consumption, specifically the fructose component, on adipose tissue and liver metabolism as both of these organs are key plays in metabolic health; dysregulation of one or both organs has been shown to impact in increased risk of chronic metabolic disease. Surprisingly, given strong positive association between free sugar intake and adiposity, very little is known about the effect and metabolism of fructose by adipose tissue. The findings of this work may aid the development of other treatment options for adipose tissue and liver mediated chronic metabolic diseases.

In addition to the academic beneficiaries described in the previous section, this research will be of benefit to policy makers, the food industry, and the general population. Initiatives such as the Responsibility Deal rely on evidence-based dietary guidelines and policies to ensure that the food industry make the optimum changes to improve the health benefits of the products they manufacturer. More evidence is therefore needed on the impact of specific constituents of foods on relevant health outcomes.

It is also vital that consumers have access to the best available evidence to help them make informed choices as to which foods and products to consume. In particular, the recent media coverage of the controversy on the role of sugars in health causes real difficulty for the consumer to make these decisions. It is therefore vital that research directly addresses these controversies to provide evidence to clarify the impact of dietary components on health. Press releases of the study results, along with the study authors providing journalists with briefings and interviews will encourage accurate reporting to the public, with clear take home messages. Researchers will also explore the opportunity to speak to interested patient groups, where dietary advice may be advantageous.