REVing-down: targeting the circadian clock in metabolic disease

REVing-down：针对代谢疾病中的生物钟

• 批准号: MR/P00279X/1
• 负责人: David Bechtold
• 金额: $ 73.86万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP00279X%2F1
• 关键词: REVing; down; targeting; circadian; clock

Obesity and diabetes are major threats to public health, and the incidence of both conditions continues to rise. Non-surgical intervention strategies including lifestyle modification are generally ineffective due to poor compliance, and current pharmacological options are plagued by poor efficacy and adverse side effects. Novel strategies and therapeutic targets are needed. Human and animal studies have shown that adipose tissue inflammation is driving factor in the progress of obesity to life-threatening conditions, such as diabetes and cardiovascular disease. White adipose tissue (WAT) is an essential energy buffer, balancing energy storage and release during natural cycles of fasting and feeding. Chronic positive energy balance leads to expansion (hypertrophy) of the tissue, and this state can result in adipocyte dysfunction. Consequential to WAT hypertrophy there is a major shift in the immune system within the adipose tissue; where immune cells which are normally beneficial to adipocyte function (eg iNKT and ILC2 cells) are replaced by pro-inflammatory immune cells, such as inflammatory monocytes and macrophages. It is this inflammatory state which perpetuates WAT dysfunction, and drives dyslipidaemia, insulin resistance and adipocyte cell death. The challenge is to identify events that signal the transition from normal 'healthy' fat storage to adipose dysfunction and inflammation.We have recently demonstrated in mice that lack of the protein REVERBa predisposes to efficient adipocyte function and resulting WAT hypertrophy. Strikingly, although fat mass is increased they do not show the expected reduced insulin sensitivity or high levels of adipose tissue inflammation normally associated hypertrophic adipose tissue. The mice also show an elevated production of adiponectin - a hormone produced by healthy adipose tissue, and known to have many beneficial metabolic effects in humans. This indicates that REVERBa plays an important role in the adaption of WAT during obesity. In this project, we want to understand how REVERBa controls WAT function, and in particular elucidate how REVERB acting in adipocytes, regulates WAT immune function to attenuate obesity-related inflammation and insulin resistance.To achieve this, we will use novel genetic targeting in mice to manipulate REVERBa expression and activity specifically in adipocytes. This will allow us to define how REVERBa drives adipocyte function under normal circumstances and during obesity to promote/attenuate the development of tissue inflammation and insulin-resistance. We will also define mechanisms though which REVERBa controls adiponectin production (a valuable therapeutic target).Exploiting this unique model, we will next characterize how immune cell dynamics differ between mice that develop obesity related inflammation and insulin resistance, with those that remain insulin-sensitive in the face of obesity. Using state-of-the-art imaging, cell sorting and genomic techniques, we will not only identify and quantify immune populations, but also determine their relative state of activation. This is important as it goes beyond the immediate impact of REVERBa to identify cells/events that signal more broadly, the development of WAT dysfunction.Alongside animal models, we will similarly define adipose-immune dynamics in visceral adipose collected from obese patients undergoing bariatric surgery and normal weight controls. This will determine which cells and events are common in the progression of obese WAT to an inflamed insulin-resistant state in both humans and mice. Importantly, we will determine whether target pathways are amenable to pharmacological manipulation in human WAT using drugs that increase or decrease REVERBa activity. The parallel nature of these studies will allow important pathways to be cross validated between human and mouse tissues, and greatly increase our ability to identify new strategies in the fight against obesity-related disease.

肥胖和糖尿病是对公共卫生的主要威胁，这两种疾病的发病率继续上升。包括生活方式改变在内的非手术干预策略由于依从性差而通常无效，并且目前的药理学选择受到疗效差和不良副作用的困扰。需要新的策略和治疗靶点。人类和动物研究表明，脂肪组织炎症是肥胖发展到危及生命的疾病（如糖尿病和心血管疾病）的驱动因素。白色脂肪组织（WAT）是一种重要的能量缓冲器，在禁食和进食的自然周期中平衡能量储存和释放。慢性正能量平衡导致组织扩张（肥大），这种状态可能导致脂肪细胞功能障碍。由于WAT肥大，脂肪组织内的免疫系统发生重大转变;其中通常有益于脂肪细胞功能的免疫细胞（例如iNKT和ILC 2细胞）被促炎免疫细胞（例如炎性单核细胞和巨噬细胞）取代。正是这种炎症状态使WAT功能障碍持续存在，并驱动血脂异常、胰岛素抵抗和脂肪细胞死亡。挑战在于确定从正常的“健康”脂肪储存到脂肪功能障碍和炎症的信号事件。我们最近在小鼠中证明，缺乏蛋白质REVERBa容易导致有效的脂肪细胞功能和导致WAT肥大。引人注目的是，尽管脂肪量增加，但它们并没有显示出预期的胰岛素敏感性降低或通常与肥大脂肪组织相关的高水平脂肪组织炎症。这些小鼠还显示出脂联素的产生增加，脂联素是一种由健康脂肪组织产生的激素，已知对人类有许多有益的代谢作用。这表明REVERBa在肥胖期间WAT的适应中起重要作用。在这个项目中，我们希望了解REVERBa如何控制WAT功能，特别是阐明REVERB如何在脂肪细胞中起作用，调节WAT免疫功能以减轻肥胖相关的炎症和胰岛素抵抗。为了实现这一目标，我们将在小鼠中使用新的遗传靶向来操纵REVERBa在脂肪细胞中的表达和活性。这将使我们能够确定REVERBa如何在正常情况下和肥胖期间驱动脂肪细胞功能，以促进/减弱组织炎症和胰岛素抵抗的发展。我们还将确定REVERBa控制脂联素产生的机制（一种有价值的治疗靶点）。利用这一独特的模型，我们接下来将描述免疫细胞动力学在发生肥胖相关炎症和胰岛素抵抗的小鼠与那些在肥胖面前保持胰岛素敏感的小鼠之间的差异。使用最先进的成像，细胞分选和基因组技术，我们不仅可以识别和量化免疫群体，还可以确定它们的相对激活状态。这一点很重要，因为它超越了REVERBa的直接影响，以确定更广泛的信号细胞/事件，WAT功能障碍的发展。除了动物模型，我们将同样定义从接受减肥手术和正常体重控制的肥胖患者收集的内脏脂肪中的脂肪免疫动力学。这将确定哪些细胞和事件在人类和小鼠中肥胖WAT向炎症胰岛素抵抗状态的进展中是常见的。重要的是，我们将确定靶向途径是否适合于使用增加或减少REVERBa活性的药物在人WAT中进行药理学操作。这些研究的平行性质将允许在人类和小鼠组织之间交叉验证重要的途径，并大大提高我们确定对抗肥胖相关疾病的新策略的能力。

项目成果

HNF4A is required to specify glucocorticoid action in the liver

• DOI: 10.1101/2021.04.10.438998
• 发表时间: 2021-04
• 期刊: bioRxiv
• 作者: A. L. Hunter;T. Poolman;Donghwan Kim;F. Gonzalez;D. Bechtold;A. Loudon;M. Iqbal;D. Ray

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells

红细胞日常血红蛋白氧化节律的机制和生理功能

• DOI: 10.1101/2021.10.11.463714
• 发表时间: 2021
• 作者: Beale A

HNF4A modulates glucocorticoid action in the liver.

• DOI: 10.1016/j.celrep.2022.110697
• 发表时间: 2022-04-19
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Hunter, A. Louise;Poolman, Toryn M.;Kim, Donghwan;Gonzalez, Frank J.;Bechtold, David A.;Loudon, Andrew S., I;Iqbal, Mudassar;Ray, David W.
• 通讯作者: Ray, David W.

REVERBa couples the circadian clock to hepatic glucocorticoid action.

• DOI: 10.1172/jci96138
• 发表时间: 2018-10-01
• 期刊: The Journal of clinical investigation
• 作者: Caratti G;Iqbal M;Hunter L;Kim D;Wang P;Vonslow RM;Begley N;Tetley AJ;Woodburn JL;Pariollaud M;Maidstone R;Donaldson IJ;Zhang Z;Ince LM;Kitchen G;Baxter M;Poolman TM;Daniels DA;Stirling DR;Brocker C;Gonzalez F;Loudon AS;Bechtold DA;Rattray M;Matthews LC;Ray DW
• 通讯作者: Ray DW