Impact of intermittent cold exposure on function of brown/white adipose tissue and metabolic consequences of obesity

The molecular pathogenesis of obesity-associated dyslipidaemia, insulin resistance and non-alcoholic fatty liver disease (NAFLD) is not fully understood. An imbalance of hepatic export and synthesis of free fatty acids and triglycerides in the setting of insulin resistance leads to macrovesicular and microvesicular steatosis. A final common pathway of hepatocellular damage involves inflammatory cells, cytokine release and the activation of fibrogenic effector cells, leading to fibrosis which is the main outcome determinant. Lifestyle change is the only proven effective treatment for paediatric NAFLD, but is only 30% successful at disease reversal; therefore, new interventions are needed. Children/young people (CYP) with NAFLD are an excellent population in which to study underlying mechanisms and interventions to correct disease progression as they are largely unaffected by other environmental influences, e.g. alcohol.
Evidence that brown adipose tissue (BAT) activation causes weight loss, improved lipids/glycaemia in mice/humans. BAT uses nutrients to produce heat via the action of uncoupling protein-1 (UCP1) in response to cold and feeding. Furthermore, regions of WAT can be induced to gain the molecular and functional characteristics of BAT, termed 'browning', resulting in increased thermogenic capacity. BAT is increasingly recognised as an endocrine organ mediating crosstalk with other organs, thereby altering whole body metabolism. However, comparatively little is known about how obesity and sex affect BAT function.
Intermittent cold exposure (ICE) protocols activate BAT and improve glucose homeostasis in obese mice and humans, and thus may be useful in treating obesity-related disorders. In mice cold exposure alters hepatic lipid metabolism with reduced hepatic lipogenic gene expression, and upregulated bile acid synthesis via Cyp7a1, resulting in increased hepatic and faecal bile acid excretion. In humans, BAT activity is inversely related to hepatic fat content. However, there are no published studies in humans that have investigated the influence of intermittent cold exposure on hepatic steatosis. This will be the focus of this project. Paediatric populations have a significantly higher prevalence of BAT relative to adults. This makes increasing BAT activity an attractive target to reduce obesity and associated co-morbidities, e.g. NAFLD, in CYP.
Murine studies have also demonstrated that cold exposure alters the composition of gut microbiota. When 'cold microbiota' are transplanted to germ-free mice, they promote WAT browning and improve insulin sensitivity, suggesting that one mechanism underlying ICE-mediated improvement in metabolic syndrome is modification of a microbiota-liver-BAT axis. This project will study the impact of ICE on gut microbiota and metabolites.
Our pilot data using a cooling jacket designed by Paxman Coolers Ltd, indicate that ICE activates BAT. We are currently designing novel MRI analysis protocols in collaboration with Professors Hajnal, Edwards, Price and Charles-Edwards (KCL/GSTT), and Thomas (Westminster University). The student will work with this team alongside clinical academics (Williamson and Dhawan) to study BAT/WAT/liver phenotypes in ICE exposed children/young people with NAFLD.
This project will address the hypothesis that intermittent cold exposure (ICE) actives brown adipose tissue and/or causes browning of white adipose tissue, and this approach can be used to treat adverse health outcomes in obesity-associated metabolic syndrome.
The primary research question is, 'What is the impact of intermittent cold exposure on metabolic consequences of obesity in young people with non-alcoholic fatty liver disease and in a diet-induced obesity mouse model.