A novel model of AMPK-mediated obesity involving the gamma2 subunit

与世界其他许多地区一样，英国面临着肥胖症和2型糖尿病患病率的大幅上升，尽管社会和医学越来越多地认识到体重增加在推动代谢性疾病方面的重要性。2010年，刚刚超过四分之一的英国成年人被归类为肥胖，政府预测，到2050年，超过一半的英国成年人会变得肥胖。英国被诊断患有糖尿病的人数已经从1996年的140万人增加到今天的290万人，预计到2025年将达到400多万人。肥胖和糖尿病的并发症包括当今影响工业化社会的一些最普遍和最严重的疾病，包括心脏病、高血压、中风、癌症、视力障碍和关节疾病，可能导致残疾、收入损失、预期寿命缩短(估计减少9年)，以及对医疗体系的巨大影响。肥胖和2型糖尿病都是慢性代谢性疾病，反映了个体的遗传、行为和环境(例如食物摄入量和体力活动)之间的复杂相互作用。典型的减肥策略包括试图通过节食和锻炼来改变生活方式，但这些策略很难实施，甚至更难维持，这促使人们使用额外的、更有效的治疗策略。后者包括药物治疗和减肥(减肥)手术。尽管针对特定患者的减肥手术缓解甚至解决疾病的前景日益明朗，但目前医疗体系为所有受影响患者中不到一小部分人提供减肥手术的能力有限(英国每年进行6000例手术)，再加上现有肥胖症药物疗法的长期疗效和安全性较差，促使人们积极寻找替代药物治疗方案。一个越来越有吸引力的分子靶点是蛋白质AMP激活的蛋白激酶(AMPK)，它现在被认为是作用于主要类别的抗糖尿病药物，尽管是间接的，包括二甲双胍和噻唑烷二酮类。AMPK的激活会导致多种代谢效应，并被认为是上述药物的许多好处的基础。因此，人们对AMPK的直接激活剂可能为肥胖和糖尿病的全球流行提供急需的、有效的治疗策略的可能性越来越感兴趣。为了实现这一目标，并设计基于合理的新疗法来治疗这些代谢紊乱，越来越有必要更好地了解AMPK的生物学，关于调节全身能量平衡，特别是它在大脑调节食欲方面的作用。另一个关键的悬而未决的问题是，在全身激活AMPK可能带来的长期风险-收益情况。现有的涉及AMPK的科学模型通常采用“功能丧失”或基因“敲除”的方法，即AMPK酶复合体的一个组成部分在基因上被删除。相反，我们开发了一个功能获得模型，利用基因靶向在AMPK的能量传感器亚单位，即Gamma2亚单位中诱导精确的激活遗传改变。我们的初步发现表明，通过Gamma2亚单位的慢性全身AMPK激活对包括大脑和胰腺在内的关键代谢器官既有有利的影响，也有不利的影响。在这些结果的基础上，一系列分子、细胞和生理技术在该模型中的详细应用有望对慢性AMPK激活的长期风险-收益情况产生新的见解，这对于基于AMPK系统的合理代谢疗法的设计至关重要。

In common with much of the rest of the world, the UK is facing a massive increase in the prevalence of obesity and type 2 diabetes mellitus despite growing societal and medical awareness of the importance of weight gain in driving metabolic disease. In 2010, just over a quarter of adults in the UK were classed as obese, with government predictions of over half of all UK adults becoming obese by 2050. The number of people diagnosed in the UK with diabetes has increased from 1.4 million in 1996 to 2.9 million today, and is projected to reach over 4 million by 2025. The complications of obesity and diabetes include some of the most prevalent and serious diseases affecting industrialised societies today, including heart disease, hypertension, stroke, cancer, visual impairment and joint disease, with potential associated disability, loss of earnings, reduction in life expectancy (by an estimated 9 years) and huge impact on the healthcare system. Both obesity and type 2 diabetes are chronic metabolic diseases reflecting a complex interaction between an individual's genetics, behaviour and environment (e.g. food intake and physical activity). Typical weight-loss strategies include an attempt at modification of lifestyle through dieting and exercise, but these can be frustratingly difficult to implement and even harder to maintain, prompting the use of additional, more effective treatment strategies. The latter has included medication as well as weight-loss (bariatric) surgery. Despite the increasingly clear prospect of disease alleviation or even resolution with bariatric surgery for selected patients, the limited capacity of current healthcare systems to offer it to more than a small proportion of all those affected (with 6000 procedures performed annually in the UK), coupled with the poor long-term efficacy and safety of established drug treatments for obesity, has prompted an intense search for alternative drug therapeutic options. One increasingly attractive molecular target is the protein AMP-activated protein kinase (AMPK), which has now been recognised as being acted upon, albeit indirectly, by major classes of antidiabetes drugs, including metformin and the thiazolidinediones. Activation of AMPK leads to multiple metabolic effects and is thought to underlie much of the aforementioned drug's benefits. Accordingly, there is growing intense interest in the possibility that direct activators of AMPK may provide much needed, effective treatment strategies for the worldwide epidemic of obesity and diabetes.To realise this aim and design rationally-based, novel therapies for the treatment of these metabolic disorders, there is a growing imperative to better understand the biology of AMPK with regard to the regulation of whole-body energy balance, in particular its role in appetite regulation by the brain. A further key unanswered question is the potential long-term risk-benefit profile conferred by activating AMPK across the entire body. Existing scientific models involving AMPK have generally adopted a 'loss of function' or gene 'knock-out' approach, whereby a component of the AMPK enzyme complex is genetically deleted. In contrast, we have developed a 'gain of function' model utilising gene-targeting to induce a precise activating genetic alteration in the energy-sensor subunit of AMPK, namely the gamma2 subunit. Our initial findings suggest that chronic, whole-body AMPK activation via the gamma2 subunit has both beneficial and adverse effects in key metabolic organs, including the brain and pancreas. Building on these results, the detailed application of a range of molecular, cellular and physiological techniques to this model is expected to yield new insights into the long-term risk-benefit profile of chronic AMPK activation, vital to the design of rational metabolic therapies based on the AMPK system.