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

间歇性寒冷暴露对棕色/白色脂肪组织功能的影响和肥胖的代谢后果

• 批准号: 2749764
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2749764
• 关键词: Impact; intermittent; cold; exposure; function

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.

肥胖相关血脂异常、胰岛素抵抗和非酒精性脂肪肝（NAFLD）的分子发病机制尚未完全清楚。在胰岛素抵抗的情况下，肝脏输出和游离脂肪酸和甘油三酯合成的不平衡导致大泡和微泡脂肪变性。肝细胞损伤的最后一个常见途径涉及炎性细胞、细胞因子释放和致纤维化效应细胞的活化，导致纤维化，这是主要的结果决定因素。生活方式的改变是唯一被证明有效的治疗儿童NAFLD，但只有30%的成功逆转疾病，因此，需要新的干预措施。患有NAFLD的儿童/青少年是研究纠正疾病进展的潜在机制和干预措施的优秀人群，因为他们在很大程度上不受其他环境影响，例如酒精。棕色脂肪组织（BAT）激活导致小鼠/人类体重减轻、脂质/血脂改善的证据。BAT通过解偶联蛋白-1（UCP 1）的作用利用营养物质产生热量，以应对寒冷和进食。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”，导致产热能力增加。BAT越来越被认为是一种内分泌器官，介导与其他器官的串扰，从而改变全身代谢。然而，关于肥胖和性别如何影响BAT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，因此可用于治疗肥胖相关疾病。在小鼠中，冷暴露改变肝脏脂质代谢，降低肝脏脂肪生成基因表达，并通过Cyp 7a 1上调胆汁酸合成，导致肝脏和粪便胆汁酸排泄增加。在人类中，BAT活性与肝脏脂肪含量呈负相关。然而，目前还没有发表的人类研究调查间歇性寒冷暴露对肝脏脂肪变性的影响。这将是该项目的重点。儿科人群的最佳可得技术患病率明显高于成人。这使得增加BAT活性成为减少肥胖和相关并发症（例如NAFLD）的有吸引力的目标。鼠类研究还表明，寒冷暴露会改变肠道微生物群的组成。当“冷微生物群”移植到无菌小鼠时，它们促进WAT布朗宁并提高胰岛素敏感性，这表明ICE介导的代谢综合征改善的一种机制是微生物群-肝脏-BAT轴的修饰。该项目将研究ICE对肠道微生物群和代谢物的影响。我们的试验数据使用由帕克斯曼冷却器有限公司设计的冷却夹套，表明ICE激活BAT。我们目前正在与Hajnal、Edwards、Price和Charles-Edwards（KCL/GSTT）以及托马斯（威斯敏斯特大学）教授合作设计新型MRI分析方案。学生将与临床学者（威廉姆森和Dhawan）一起与该团队合作，研究ICE暴露的NAFLD儿童/年轻人的BAT/WAT/肝脏表型。该项目将解决间歇性冷暴露（ICE）激活棕色脂肪组织和/或导致白色脂肪组织布朗宁的假设，这种方法可用于治疗肥胖相关代谢综合征的不良健康结果。主要的研究问题是，间歇性寒冷暴露对患有非酒精性脂肪肝的年轻人和饮食诱导的肥胖小鼠模型中肥胖的代谢后果有什么影响。