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

肥胖现在是世界大部分地区的地方病，并将在未来几十年成为公共卫生的最大挑战。虽然由于生物力学效应，肥胖会导致健康问题，但最大的威胁是肥胖相关的代谢紊乱，它会导致胰岛素抵抗和2型糖尿病、血脂异常以及心血管疾病。现在人们认识到，白色脂肪组织(WAT)中储存有缺陷的脂肪与肥胖症代谢紊乱的严重程度直接相关，特别是与胰岛素抵抗和最终糖尿病的发展有关。然而，目前还不清楚是什么导致了WAT功能障碍，以及这是如何导致代谢性疾病的。我们最近确定了一种模型，在该模型中，肥胖症与WAT炎症升高无关(Hand等人2014年；Hunter等人2020年)。具体地说，缺乏核激素受体(NHR)REV-ERB的小鼠即使在标准饮食中保持，也会变得非常肥胖。然而，与肥胖的WT小鼠形成鲜明对比的是，这些基因敲除小鼠的WAT显示脂肪细胞肥大，没有预期的炎症细胞涌入，更重要的是没有失去胰岛素敏感性。我们认为，失去REV-ERBA可以增加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，生物钟是WAT中连接代谢和炎症反应的关键节点，可能是该组织与肥胖相关的病理的中心。目前的提议将决定这一引人注目且重要的表型的基础。研究将表征在正常和肥胖状态下时钟对脂肪组织床内驻留和浸润性炎症细胞分布的影响。这项工作将受益于全球和组织特定的时钟靶向(例如，ADIPO-CRExReVerflx；AdipoCRExBMal1Flox)，以及在分析炎症细胞连接和激活状态方面的本地专业知识。重要的是，遗传和饮食操作将伴随着体内代谢状态、脂质处理和胰岛素/葡萄糖动态平衡的评估。为了研究脂肪细胞和/或炎症细胞(最明显的是巨噬细胞)内的昼夜生物钟作用于局部组织炎症和胰岛素抵抗的机制，体内的工作将得到细胞和组织培养的支持，包括共培养模型。我们的许多转基因品系携带时钟驱动的荧光素酶报告，允许实时评估体内或培养中的昼夜节律功能。免疫细胞特性将受益于当地的专业知识和最近在单细胞转录图谱方面的大量投资。多学科团队利用动物生理学和新陈代谢(Bechtell)、免疫学(Cruickshank)和计算生物学(Iqbal)的专业知识。候选人将在贝克泰尔德博士的实验室工作，在那里他们还接受手术方法和整个动物生理监测方面的强化培训。贝克泰尔实验室在生理和代谢途径的活体表征、小动物手术、行为和生理评估等方面拥有丰富的经验。SSA将极大地增强学生的活体培训经验和研究潜力。多学科团队和项目一起为成功的申请者提供了一个极好的培训机会。由于高端的体内培训和尖端的体外细胞图谱，候选人将在未来生命科学的任何方面的研究生涯中处于有利地位。我们的团队得到了多笔巨额外部资助的支持，许多博士后科学家、在校博士生和技术支持--从而为候选人提供了一个充满活力和支持的环境。

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.