Circadian regulation of adipose tissue; the role of the myeloid system

脂肪组织的昼夜节律调节；

• 批准号: 2595732
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2595732
• 关键词: Circadian; regulation; adipose; tissue; role

Importance: Maintenance of energy balance and metabolic health is emerging as a major challenge of our time. The consequences of obesity include cardiovascular and metabolic disease (e.g. type 2 diabetes), as well as increased cancer, musculoskeletal (e.g. osteoarthritis), and infectious disease risk, notably coronavirus mortality. Therapeutic approaches to body weight regulation have focussed on appetitive pathways in the brain or nutrient absorption in the gut; with neither approach yielding adequate success. Therefore, new, effective and safe strategies are needed. Most systemic and cellular energy metabolism is closely tied into the regulatory network of the circadian clock. Notably, ribosome biogenesis shows strong daily oscillations that are regulated by both circadian and feeding rhythms, acting through the translation control (e.g. ribosomal protein and translation factor biosynthesis). Rhythmicity also affects mitochondrial dynamics (synthesis, fission/fusion) and oxidative activity, in part due to the close coupling between the clock and regulators of mitochondrial biogenesis including Pgc1a. Given the role played by timing in energy metabolism it is essential to consider circadian factors in analysis of adipose function. Hypotheses: Regulation of timing in adipose tissue beds reflects inputs from the sympathetic nervous system, which is closely linked to the central brain clock in the suprachiasmatic nucleus, and flows external light-dark cycles; and the clock in the adipocyte which follows feeding and fasting cycles. This opens the possibility of internal desynchrony, with circadian oscillators running out of phase in adipose tissue, with unknown consequences.Resources: we will use mouse as a pre-clinical model. We have a range of transgenic mice with circadian clock components floxed, to allow tissue-specific gene knockout. We can manipulate light cycles, and feeding times, in order to drive changes in circadian phase in adipocytes, and the sympathetic nervous system. We can use tissue specific TNFa expression to drive inflammation to adipose beds, to model conditions of inflammation seen in human obesity, or in human adipose beds in patients with systemic inflammation eg rheumatoid arthritis.Plans: We will analyse the impact of circadian misalignment on adipocyte and myeloid cell compartments in adipose tissue, focussed on circadian function, gene expression, and energy metabolic function (lipolysis/lipogenesis, mitochondrial function).We will initially focus on disrupting circadian function in macrophages, to target the adipose tissue associated macrophage, and the newly-identified sympathetic nervous system associated macrophages (discovered by Dr A Domingos).We will then move to light cycle manipulation, and time-restricted feeding protocols to drive misalignment. We will block sympathetic innervation to the adipose beds using surgical denervation, and transgenic directed loss of the circadian clock in the sympathetic neurones. We can also use beta adrenergic system pharmacological blockade. We will use a new mouse model of conditional TNFa expression, confined to adipose beds by crossing adiponectin-creERET mice with a ROSA26 stop-flox TNFa mouse. This model will test the prevalent condition of adipose bed inflammation, which we can test under standard and high fat obesity conditions.We will seek to investigate cellular heterogeneity in the adipose beds and will make selective use of single cell RNA-seq and ATAC-seq, which can be done in the same cells, to establish the consequences of such misalignment for cell type-specific differentiation in adipose beds.Our links with NN will mainly focus on scientific discussions, and the commercial context of our models, and our findings. This will be facilitated by mutually agreed project update meetings. Depending on progress we may seek specific collaborative arrangements, on a case-by-case basis

重要性：维持能量平衡和代谢健康正在成为我们这个时代的一项重大挑战。肥胖的后果包括心血管和代谢疾病（例如 2 型糖尿病），以及癌症、肌肉骨骼（例如骨关节炎）和传染病风险增加，尤其是冠状病毒死亡率。体重调节的治疗方法主要集中在大脑中的食欲途径或肠道中的营养吸收。这两种方法都没有取得足够的成功。因此，需要新的、有效的和安全的策略。大多数全身和细胞能量代谢与生物钟的调节网络密切相关。值得注意的是，核糖体生物发生表现出强烈的日常振荡，受到昼夜节律和进食节律的调节，通过翻译控制（例如核糖体蛋白和翻译因子生物合成）发挥作用。节律性还影响线粒体动力学（合成、裂变/融合）和氧化活性，部分原因是时钟和线粒体生物发生调节因子（包括 Pgc1a）之间的紧密耦合。鉴于时间在能量代谢中所起的作用，在分析脂肪功能时必须考虑昼夜节律因素。假设：脂肪组织床的时间调节反映了交感神经系统的输入，交感神经系统与视交叉上核的中枢脑时钟密切相关，并流动外部明暗周期；以及脂肪细胞中遵循进食和禁食周期的时钟。这开启了内部不同步的可能性，昼夜节律振荡器在脂肪组织中异相运行，后果未知。资源：我们将使用小鼠作为临床前模型。我们拥有一系列生物钟成分被改变的转基因小鼠，以实现组织特异性基因敲除。我们可以操纵光周期和进食时间，以驱动脂肪细胞和交感神经系统昼夜节律的变化。我们可以利用组织特异性 TNFa 表达将炎症驱动到脂肪床，以模拟人类肥胖或患有系统性炎症（例如类风湿性关节炎）患者脂肪床中的炎症状况。计划：我们将分析昼夜节律失调对脂肪组织中脂肪细胞和骨髓细胞区室的影响，重点关注昼夜节律功能、基因表达和能量 代谢功能（脂肪分解/脂肪生成、线粒体功能）。我们首先将重点关注破坏巨噬细胞的昼夜节律功能，以脂肪组织相关的巨噬细胞和新发现的交感神经系统相关的巨噬细胞（由 A Domingos 博士发现）为目标。然后我们将转向光周期操纵和限时喂养方案以驱动失调。我们将通过手术去神经支配来阻断对脂肪床的交感神经支配，并通过转基因定向丧失交感神经元中的生物钟。我们还可以使用β肾上腺素能系统的药物阻断。我们将使用一种新的条件性 TNFa 表达小鼠模型，通过将脂联素-creERET 小鼠与 ROSA26 stop-flox TNFa 小鼠杂交，将其限制在脂肪床中。该模型将测试脂肪床炎症的普遍状况，我们可以在标准和高脂肪肥胖条件下进行测试。我们将寻求研究脂肪床中的细胞异质性，并将选择性地使用单细胞 RNA-seq 和 ATAC-seq（可以在相同细胞中完成）来确定这种错位对脂肪床中细胞类型特异性分化的影响。我们与 NN 的联系将主要集中在 科学讨论、我们模型的商业背景以及我们的发现。双方商定的项目更新会议将促进这一点。根据进展情况，我们可能会根据具体情况寻求具体的合作安排