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

肥胖相关血脂异常、胰岛素抵抗和非酒精性脂肪性肝病(NAFLD)的分子发病机制尚不完全清楚。在胰岛素抵抗的背景下，肝脏出口和游离脂肪酸和甘油三酯合成的失衡会导致大泡和微泡脂肪变性。肝细胞损伤的最终共同途径涉及炎症细胞、细胞因子的释放和纤维化效应细胞的激活，导致纤维化，这是主要的结局决定因素。改变生活方式是儿童NAFLD唯一被证明有效的治疗方法，但在逆转疾病方面只有30%的成功率；因此，需要新的干预措施。患有NAFLD的儿童/青年(CYP)是研究潜在机制和干预措施以纠正疾病进展的优秀人群，因为他们基本上不受其他环境影响，如酒精。有证据表明，棕色脂肪组织(BAT)激活会导致体重减轻，改善小鼠/人类的血脂/血糖。蝙蝠利用营养物质通过解偶联蛋白-1(UCP1)的作用来产生热量，以响应寒冷和取食。此外，Wat的区域可以被诱导以获得BAT的分子和功能特征，称为‘褐变’，从而增加产热能力。蝙蝠越来越被认为是一种内分泌器官，调节与其他器官的串扰，从而改变全身的新陈代谢。然而，关于肥胖和性别如何影响蝙蝠功能的研究相对较少。间歇性冷暴露(ICE)方案激活BAT并改善肥胖小鼠和人类的葡萄糖稳态，因此可能对治疗肥胖相关疾病有用。在小鼠中，冷暴露改变了肝脏的脂肪代谢，降低了肝脏造脂基因的表达，并通过Cyp7a1上调了胆汁酸的合成，导致肝脏和粪便胆汁酸排泄增加。在人类中，BAT活动与肝脏脂肪含量成反比。然而，目前还没有发表的人类研究调查间歇性冷暴露对肝脏脂肪变性的影响。这将是这个项目的重点。与成人相比，儿童人群的BAT患病率明显更高。这使得增加BAT活动成为一个有吸引力的目标，以减少肥胖和相关的共病，例如在CYP中的NAFLD。小鼠的研究也表明，寒冷暴露会改变肠道微生物区系的组成。当‘冷微生物群’被移植到无菌小鼠身上时，它们促进了Wat褐变并改善了胰岛素敏感性，这表明ICE介导的代谢综合征改善的一个机制是修改微生物群-肝脏-蝙蝠轴。本项目将研究冰对肠道微生物区系和代谢产物的影响。我们使用Paxman Coolers有限公司设计的冷却夹克的飞行员数据表明，ICE激活了BAT。我们目前正在与哈纳尔、爱德华兹、普赖斯和查尔斯-爱德华兹(KCL/GSTT)教授以及威斯敏斯特大学的托马斯教授合作，设计新的MRI分析方案。这名学生将与临床学者(威廉姆森和达万)一起与这个团队合作，研究ICE暴露的患有NAFLD的儿童/年轻人的BAT/WAT/肝脏表型。该项目将解决这样的假设，即间歇性冷暴露(ICE)激活棕色脂肪组织和/或导致白色脂肪组织褐化，该方法可用于治疗肥胖相关代谢综合征的不良健康后果。主要的研究问题是，在患有非酒精性脂肪性肝病的年轻人和饮食诱导肥胖的小鼠模型中，间歇性寒冷暴露对肥胖的代谢后果有什么影响。

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.