BUD23 drives system-wide adaptations to energy metabolism

维持我们的代谢健康正在成为我们这个时代的一个主要挑战。肥胖的后果包括心血管和代谢疾病（如2型糖尿病），以及增加癌症、肌肉骨骼疾病（如骨关节炎）和传染病风险，特别是冠状病毒死亡率。体重调节的治疗方法侧重于大脑中的食欲调节途径或肠道中的营养吸收；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。我们研究了一种相对未知的酶BUD23在调节体重、身体成分和能量代谢中的作用。人类的遗传研究已经将BUD23及其伴侣TRMT112与肥胖和循环甘油三酯升高联系起来，我们在小鼠身上的研究表明，该因子的作用可能对脂肪组织和肝脏特别有影响，这是调节我们对食物摄入、禁食和肥胖反应的关键部位。BUD23是核糖体成熟的一种成熟且保守的调节因子，核糖体成熟是细胞中负责制造蛋白质的成分。迄今为止，我们的工作表明，BUD23对核糖体功能的影响是选择性的，对线粒体（细胞内能量代谢的关键部位）的产生和功能有特别强烈的影响。事实上，我们发现从小鼠脂肪组织中特异性地删除BUD23会重新编程能量储存和消耗（使用）的平衡，并导致体脂比例显著降低。在这篇论文中，我们将全面定义BUD23在指导关键组织代谢中的作用，以获得治疗见解和靶过程，并描述其基本机制（从翻译效率到线粒体功能）。这项工作符合MRC在营养和肥胖方面的优先事项。具体来说，我们将研究BUD23在脂肪和肝脏中的表型，并研究这些组织中的BUD23如何调节对高脂肪饮食的反应。我们将探索BUD23作用与细胞代谢生物钟之间的联系，因为我们迄今为止的证据表明，当BUD23在脂肪中被删除时，能量底物利用的典型变化在昼夜节律时间中显著丧失。我们还将通过基因靶组织的蛋白质组学和功能评估来研究BUD23与线粒体动力学和活性之间的联系。最后，我们将使用核糖体分析来确定对mRNA翻译效率的选择性影响的机制，我们认为这是在mRNA序列中编码的。我们将整合mRNA表达，mRNA翻译和稳态蛋白质丰度，使用计算方法构建RNA生物学如何影响能量代谢的集成模型，以及这些过程如何可能成为治疗目标。

Maintenance of our metabolic health is emerging as a major challenge of our time. The consequences of obesity include cardiovascular and metabolic disease (eg type 2 diabetes), as well as increased cancer, musculoskeletal (eg osteoarthritis), and infectious disease risk, notably corona virus mortality. Therapeutic approaches to body weight regulation have focused on appetite regulating pathways in the brain or nutrient absorption in the gut; with neither approach yielding adequate success. Therefore, new, effective and safe strategies are needed. Our proposal investigates the function of relatively unknown enzyme, BUD23, in regulating body weight, body composition and energy metabolism. Genetic studies in humans have associated BUD23 and its partner TRMT112 to obesity and elevated circulating triglycerides, and our studies in mice suggest that the action of this factor may be particularly influential in adipose tissue and the liver, key sites regulating our response to food intake, fasting and obesity. BUD23 is an established and conserved regulator of ribosomal maturation, the component of the cell responsible for making proteins. Our work to date suggests that the impact of BUD23 on ribosome function is selective, and has a particularly strong influence over production and functioning of mitochondria (a critical site of energy metabolism within our cells). Indeed, we find that deletion of BUD23 specifically from adipose tissue in mice re-programmes the balance of energy storage and expenditure (use), and results in a significantly lower proportion of body fat. In this proposal, we will fully define the role of BUD23 in directing metabolism in key tissues to gain therapeutic insight and target processes, and delineate the fundamental mechanisms (from translation efficiency to mitochondrial function). This work is in line with MRC priorities in nutrition and obesity.Specifically, we will investigate the phenotype of BUD23 in adipose and liver, and examine how BUD23 in these tissues regulates responses to high fat diet. We will explore links between BUD23 action and the cellular metabolic circadian clock, as our evidence to date reveals a striking loss of the typical change in energy substrate utilisation through circadian time when BUD23 is deleted in adipose. We will also investigate links between BUD23 and mitochondria dynamics and activity through proteomic and functional assessment in genetically targeted tissues. Finally, we will use ribosome profiling to identify the mechanism responsible for selective impacts on mRNA translation efficiency, which we think are encoded in mRNA sequences. We will integrate mRNA expression, mRNA translation, and steady-state protein abundance, using computational approaches to build an integrated model of how RNA biology affects energy metabolism, and how these processes may be therapeutically targeted.