Investigating the mechanisms in sympathetic neurons that link sleep to obesity

肥胖是影响全球许多人的一个主要健康问题。不幸的是，治疗肥胖症的选择有限，包括手术和抑制食欲的药物，这可能是昂贵的和不可逆转的。改变生活方式和节食的成本较低，但往往无效，因为它们可以导致能量消耗的补偿性减少，使长期减肥变得困难。这是因为当我们减少食物摄入量时，我们身体的新陈代谢会适应能量的节省，这可以抵消节食期间的体重减轻。为了克服这个问题，我们正在试图了解代谢适应禁食背后的生物学机制。这项研究的一个重要方面是研究生热的作用，这是一个以热的形式耗散能量的过程，以及休息和交感神经元如何影响它。最近在人类和小鼠身上的研究表明，肾上腺素能β2(ADRB2)激动剂可以促进产热和能量消耗，潜在地使人更容易减肥。本研究提案的目标是更好地了解代谢对禁食的适应背后的分子机制，以及ADRB2在产热和能量消耗中的作用。这项研究将使用小鼠来研究ADRB2激动剂是否可以减轻对禁食的代谢适应，以及这种影响是否依赖于交感神经元中控制生热脂肪组织的ADRB2的功能。我们还旨在了解睡眠不足是否会改变对禁食的新陈代谢适应，以及这是否与交感神经元中ADRB2信号的降低和热源性脂肪组织中的交感神经变性有关。我们认为这项研究很重要，因为众所周知，睡眠不足的人和动物会增加更多的体重。总而言之，这项研究旨在为有效、安全和负担得起的肥胖症治疗新方法提供见解。通过了解禁食代谢适应背后的分子机制以及ADRB2在生热作用中的作用，其他研究人员或许能够开发出新的药物或疗法，帮助人们减肥并保持健康的生活方式。

Obesity is a major health problem that affects many people worldwide. Unfortunately, there are limited options available to treat obesity, including surgery and medications that suppress appetite, which can be expensive and irreversible. Lifestyle changes and dieting are less expensive but often ineffective because they can lead to a compensatory decrease in energy expenditure, making it difficult to lose weight in the long term. This is because when we reduce our food intake, our body's metabolism adapts to save energy, which can counteract weight loss during dieting.To overcome this problem, we are trying to understand the biological mechanisms behind metabolic adaptation to fasting. One important aspect of this research is to investigate the role of thermogenesis, a process that dissipates energy in the form of heat, and how it is affected by rest and sympathetic neurons. Recent studies in humans and mice have shown that adrenergic beta 2 (adrb2) agonists can boost thermogenesis and energy expenditure, potentially making it easier to lose weight.The goal of this research proposal is to better understand the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis and energy expenditure. The research will use mice to investigate whether adrb2 agonism can mitigate metabolic adaptation to fasting, and whether this effect is dependent on the function of adrb2 in sympathetic neurons that control thermogenic adipose tissue. We also aim to understand whether lack of rest, consequence of sleep deprivation, alters metabolic adaptation to fasting and whether this is connected to lower adrb2 signaling in sympathetic neurons and sympathetic neurodegeneration within thermogenic adipose tissue. We think that this is important to study because it is well known that humans and animals that are sleep deprived gain more weight.Overall, this research aims to provide insights into new approaches to treat obesity that are effective, safe, and affordable. By understanding the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis, other researchers may be able to develop new medications or therapies that can help people lose weight and maintain a healthy lifestyle.