The role of clock dysfunction in obesity-related inflammation and insulin resistance

生物钟功能障碍在肥胖相关炎症和胰岛素抵抗中的作用

• 批准号: 2448149
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2448149
• 关键词: role; clock; dysfunction; obesity; related

Obesity is now endemic across much of the world, and is set to become the biggest challenge to public health in the coming decades. While obesity can cause health problems as a consequence of biomechanical effects, the major threat is obesity-related metabolic disturbances, which drives insulin resistance and type-2 diabetes, dyslipidaemia, and cardiovascular disease. It is now recognised that defective lipid (fat) storage in white adipose tissue (WAT) is directly linked to the severity of metabolic disturbance in obesity, and especially the development of insulin resistance and ultimately diabetes. However, it remains unclear what causes WAT dysfunction and how this leads to metabolic disease. We have recently identified a model in which obesity is not associated by elevated WAT inflammation (Hand et al 2014; Hunter et al 2020). Specifically, mice lacking the nuclear hormone receptor (NHR), Rev-erb, become profoundly obese even when maintained on a standard diet. However, in striking contrast to obese WT mice, the WAT in these knockout mice shows adipocyte hypertrophy with none of the expected influx of inflammatory cells, and importantly without loss of insulin sensitivity. We propose that loss of REV-ERBa permits enhanced adipocyte fat storage, without resulting in adipocyte cell stress, thus limiting inflammation, and loss of insulin sensitivity. Thus, the circadian clock is a key node linking metabolic and inflammatory responses in WAT, and may be central to obesity-related pathology in this tissue. The current proposal will determine the basis for this striking, and important phenotype. Studies will characterize the impact of the clock on resident and infiltrating inflammatory cell profiles within the adipose tissue beds under normal and the obese state. This work will benefit from both global and tissue specific (e.g. adipo-CRExReverbflox; AdipoCRExBmal1flox) targeting of the clock, combined with local expertise in profiling inflammatory cell linage and activation state. Importantly, genetic and dietary manipulations will be accompanied by in vivo assessment of metabolic status, lipid handling and insulin/glucose homeostasis. To examine mechanisms through which the circadian clockwork within adipocytes and/or inflammatory cells (most notably macrophages) act to drive local tissue inflammation and insulin resistance, in vivo work will be complimented by cell and tissue culture, including co-culture models. Many of our transgenic lines carry clock driven luciferase reporters, allowing real-time assessment of circadian function both in vivo or in culture. Immune cell characterization will benefit from local expertise and substantial recent investment in single cell transcriptional profiling.The multidisciplinary team draws on expertise in animal physiology and metabolism (Bechtold), Immunology (Cruickshank) and computational biology (Iqbal). The candidate will be based in the lab of Dr. Bechtold, where they also receive intensive training in surgical approaches and whole animal physiological monitoring. The Bechtold lab has extensive experience with in vivo characterisation of circadian and metabolic pathways, small animal surgery, behavioural and physiological assessment, etc. The SSA will greatly enhance the in vivo training experience and research potential for the student.Together, the multidisciplinary team and project provides an excellent training opportunity for the successful applicant. Owing to the high end in vivo training and cutting edge ex vivo cellular profiling, the candidate will be well positioned for a future research career in any aspect of life sciences. Our grouping are supported by multiple large externally funded grants, with many post-doctoral scientist, current PhD students and technical support - thereby providing a vibrant and supportive environment for the candidate.

肥胖现在是世界上许多地方的地方病，并将成为未来几十年公共卫生面临的最大挑战。虽然肥胖会因生物力学效应而导致健康问题，但主要的威胁是肥胖相关的代谢紊乱，这会导致胰岛素抵抗和2型糖尿病、血脂异常和心血管疾病。现在认识到，白色脂肪组织（WAT）中脂质（脂肪）储存缺陷与肥胖症中代谢紊乱的严重性直接相关，特别是与胰岛素抵抗和最终糖尿病的发展直接相关。然而，目前尚不清楚是什么原因导致WAT功能障碍以及这如何导致代谢疾病。我们最近确定了一种模型，其中肥胖与WAT炎症升高无关（Hand et al 2014; Hunter et al 2020）。具体来说，缺乏核激素受体（NHR）Rev-erb的小鼠即使在维持标准饮食的情况下也会变得非常肥胖。然而，与肥胖WT小鼠形成鲜明对比的是，这些敲除小鼠中的WAT显示脂肪细胞肥大，没有预期的炎性细胞流入，重要的是没有胰岛素敏感性丧失。我们认为，REV-ERBa的缺失可以增强脂肪细胞的脂肪储存，而不会导致脂肪细胞应激，从而限制炎症和胰岛素敏感性的丧失。因此，昼夜节律钟是WAT中连接代谢和炎症反应的关键节点，并且可能是该组织中肥胖相关病理的中心。目前的建议将确定这一引人注目的重要表型的基础。研究将描述在正常和肥胖状态下，生物钟对脂肪组织床内的驻留和浸润炎性细胞谱的影响。这项工作将受益于时钟的全局和组织特异性（例如脂肪-CRexReverbflox; AdipoCRexBmal 1flox）靶向，结合分析炎症细胞谱系和激活状态的本地专业知识。重要的是，遗传和饮食操作将伴随着代谢状态、脂质处理和胰岛素/葡萄糖稳态的体内评估。为了研究脂肪细胞和/或炎性细胞（最明显的是巨噬细胞）内的昼夜节律时钟机制驱动局部组织炎症和胰岛素抵抗的机制，体内工作将通过细胞和组织培养（包括共培养模型）进行补充。我们的许多转基因系携带时钟驱动的荧光素酶报告基因，允许在体内或培养中实时评估昼夜节律功能。免疫细胞表征将受益于当地的专业知识和最近在单细胞转录谱方面的大量投资。多学科团队利用动物生理学和代谢（Bechtold），免疫学（Cruickshank）和计算生物学（Iqbal）的专业知识。候选人将在Bechtold博士的实验室工作，在那里他们还将接受手术方法和整个动物生理监测的强化培训。Bechtold实验室在生物钟和代谢途径的体内表征、小动物手术、行为和生理评估等方面拥有丰富的经验。SSA将大大增强学生的体内培训经验和研究潜力。多学科团队和项目为成功的申请人提供了绝佳的培训机会。由于高端的体内培训和尖端的离体细胞分析，候选人将在生命科学的任何方面的未来研究生涯中处于有利地位。我们的分组由多个大型外部资助的赠款支持，有许多博士后科学家，目前的博士生和技术支持-从而为候选人提供了一个充满活力和支持的环境。