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

与世界其他许多国家一样，英国正面临肥胖和2型糖尿病患病率的大幅增加，尽管社会和医学界越来越认识到体重增加在推动代谢疾病方面的重要性。2010年，英国只有超过四分之一的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将变得肥胖。在英国，糖尿病确诊人数从1996年的140万增加到今天的290万，预计到2025年将超过400万。肥胖症和糖尿病的并发症包括一些影响当今工业化社会的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），并对医疗保健系统产生巨大影响。肥胖和2型糖尿病都是慢性代谢性疾病，反映了个体遗传、行为和环境（例如食物摄入和体力活动）之间的复杂相互作用。典型的减肥策略包括尝试通过节食和锻炼来改变生活方式，但这些都很难实施，甚至更难维持，这促使人们使用额外的，更有效的治疗策略。后者包括药物治疗以及减肥（减肥）手术。尽管对选定的患者进行减肥手术的疾病缓解或甚至解决的前景越来越清楚，但目前的医疗保健系统的能力有限，无法为所有受影响的患者中的一小部分人提供减肥手术（英国每年进行6000例手术），再加上现有的肥胖药物治疗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活化蛋白激酶（AMPK），现在已被认为是主要类别的抗糖尿病药物（包括二甲双胍和噻唑烷二酮类）的作用（尽管是间接作用）。AMPK的激活导致多种代谢效应，并被认为是上述药物益处的基础。因此，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治疗策略的可能性越来越引起人们的强烈兴趣。为了实现这一目标并设计用于治疗这些代谢紊乱的基于理性的新疗法，越来越有必要更好地了解AMPK在全身能量平衡调节方面的生物学，特别是其在大脑食欲调节中的作用。另一个尚未回答的关键问题是激活AMPK在整个身体中所带来的潜在长期风险-获益特征。现有的涉及AMPK的科学模型通常采用“功能丧失”或基因“敲除”方法，即AMPK酶复合物的一种成分被遗传删除。相比之下，我们已经开发了一种“功能增益”模型，利用基因靶向诱导AMPK能量传感器亚基（即γ 2亚基）的精确激活遗传改变。我们的初步研究结果表明，通过γ 2亚基的慢性全身AMPK激活对关键代谢器官（包括大脑和胰腺）既有有益的影响，也有不利的影响。在这些结果的基础上，一系列分子，细胞和生理技术的详细应用，该模型预计将产生新的见解长期的风险-效益概况的慢性AMPK激活，至关重要的设计合理的代谢疗法的基础上AMPK系统。

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.