Title: Impact of cold exposure in conjunction with diaetary modification on metabolic regulation in children with non-alcoholic fatty liver diease
Funder: Guts UK

Abstract: Background: Obesity-associated non-alcoholic fatty liver disease (NAFLD) is now the commonest paediatric liver disease. It may progress to subsequent cirrhosis, liver failure and increased risk of cardiovascular mortality. If recognised early, there is the potential to reverse the liver injury. However, lifestyle and dietary interventions have had limited impact and new approaches are needed. We will evaluate intermittent cold exposure (ICE), in conjunction with nutrition and lifestyle advice, as an early life intervention to enhance brown adipose tissue (BAT) to ameliorate obesity-associated NAFLD in children. Our pilot data show that ICE reduces hepatic steatosis (50% reduction in fatty acids) and increases BAT fatty acid oxidation in a mouse model of NAFLD. ICE can upregulate BAT, improve dyslipidaemia and insulin sensitivity in lean adults. Children have more BAT than adults so modulation of BAT to improve NAFLD in this high-risk group is logical and timely. However, there are currently limited data on BAT induction in children as radiation has previously been required to image BAT. This project will use non-radioactive MRI-based approaches to evaluate BAT and hepatic steatosis before and after ICE. Hypothesis: ICE delivered by a cooling garment will stimulate BAT activation, causing increased lipid catabolism. This will be associated with reduced serum and hepatic lipids in children with NAFLD. Objectives: Recruit 8-12 year-old children with NAFLD and age- and sex-matched controls to perform pilot experiments to show that the study is feasible and to perform power calculations for a larger grant application. Specific study objectives are to: i) Perform MR scans to evaluate BAT size and function and liver fat fraction. ii) Evaluate use of thermal imaging to study BAT activation. iii) Measure serum markers of BAT function, glucose and lipid metabolism. iv) Evaluate the impact of ICE on these parameters. Design and methods: We have separate funds (King’s Together award) to perform focus groups in Autumn 2019 to refine the study protocol and cooling garment design, so all approvals should be in place in April 2020. We will recruit 12 children with NAFLD from the paediatric liver clinic at King’s College Hospital (KCH) and 12 age- and sex-matched controls. Participants will use a cooling garment (16oC, 1 hour/day for 5 days) alongside dietary modification. MRI scans and thermal imaging will be performed before and after ICE (day 1) and after ICE (day 5) to evaluate BAT size and activation. Liver steatosis and fibroinflammation will be evaluated using multiparametric MRI. Serum markers of BAT activation and glucose/lipid metabolism will be measured. Clinical and scientific impact: If ICE upregulates BAT and improves steatosis, lipid or glucose metabolism, we will apply for funds to perform more extensive evaluation of ICE alongside dietary modification in children and adults with NAFLD, and to understand underlying biological mechanisms by which ICE improves metabolic health. This research could open up a new field of temperature-related therapies for children of different ages and adults. It will also give new insights into the interplay between environmental modification (i.e. altered temperature), nutrition and metabolism in paediatric NAFLD.

Lay abstract: Background: One third of children aged 6-9 years are overweight or obese, and many of these children have health-related problems including high blood cholesterol, increased rates of diabetes and fatty liver disease. This project will focus on fatty liver disease in children. This is an important health problem and is now the main reason that children are seen in Paediatric Liver Clinics. Affected children have increased risks of liver cirrhosis in later life. At present the only effective way to reverse fatty liver disease is weight loss. However, most lifestyle modification programmes have not been successful. Therefore new approaches are urgently needed. We have shown that brief periods of cold exposure halve liver fat in obese mice with fatty livers. This is done by causing a particular form of fatty tissue that is called brown fat to burn calories to make heat. Recent studies in lean adults have shown that brief episodes of cold exposure activate brown fat and reduce cholesterol in the blood as well as improving diabetes markers. It is known that children have more brown fat than adults, so they are likely to have more marked responses to cold exposure than adults. Therefore, we believe the time is right to perform a pilot study of transient cold exposure in children. Questions and objectives: Does cold exposure delivered using a cooling garment (e.g. a neck wrap or a jacket), used alongside nutritional modification, cause brown fat to burn calories and therefore improve fatty liver disease in children? Does cold exposure also reduce the level of cholesterol and diabetes markers in the blood? How will it be done? A challenge for studying brown fat in the past was that the techniques used required radiation. We aim to show the activation of brown fat and the decrease in fatty liver using MRI scans/thermal imaging – safe methods that avoid radiation. We will use MRI scans to study children with fatty liver before and after they wear a cooling garment for 1 hour a day for 5 days. Blood samples will be studied to see if cholesterol or glucose measurements improve. If we show an effect, we will use the data to write a large grant application to take the work forward in children of different ages and also to study adults with fatty livers. Potential impact: If transient cold exposure improves or reverses fatty liver disease in children, or if it improves high cholesterol or diabetes markers in the blood, this could have a major impact on the metabolic health of children with obesity-related metabolic diseases. As childhood obesity is an increasing problem in the UK and worldwide the work could improve the health of a large number of people. Simple protocols to deliver brief episodes of cold therapy could be offered to high risk children (and also to adults with fatty liver if they are shown to respond). Separate ways to activate brown fat could be evaluated, e.g. with drugs, if the approach is effective at improving metabolic health.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL