Lipokines from browning adipose tissue regulate systemic metabolism to resist obesity

肥胖的特征是体内脂肪水平高，导致身体质量指数超过30。全球有超过6.5亿人患有肥胖症。肥胖会增加心血管疾病、某些癌症和2型糖尿病(T2D)的风险。考虑到受影响的人数、对他们生活质量的影响以及医疗保健的负担，找到新的治疗方法至关重要。能量平衡是我们理解新陈代谢和肥胖症等代谢性疾病的关键概念。能量摄取(食物摄入量)和能量消耗(日常生物过程/体力活动)之间的平衡决定了一个人是瘦还是胖。长期的能量不平衡，与过度摄取和减少支出相结合，导致白色脂肪组织中白色脂肪细胞内脂肪的能量储存增加，并可能导致包括肥胖和T2 D在内的代谢性疾病。许多与肥胖的发展或治疗相关的生物过程涉及脂肪组织。白色脂肪组织曾经只被认为是能量储存库，现在人们知道它是被称为脂肪因子的关键生物信号的来源，脂肪因子被释放到血液中，并与其他器官沟通，以调节全身的新陈代谢。然而，并非所有的脂肪细胞都是一样的。第二类脂肪细胞被称为棕色脂肪细胞，它们通过“燃烧”储存的脂肪来产生热量来调节体温。第三类细胞被称为米色脂肪细胞，它们可以从白色脂肪细胞(储存脂肪)的行为转变为棕色脂肪细胞的功能(燃烧脂肪)，这一过程被称为“褐变”。在人类中，米色脂肪构成了这种产热组织的大部分，但也存在于白色脂肪组织中，一旦被激活，就具有抗肥胖的作用。最近的研究，包括我们自己的研究表明，米色脂肪的几个抗肥胖特性可能是通过向血液释放信号来实现的，这些信号与肝脏和肌肉等其他组织沟通，改变其新陈代谢，从而产生非产热效应。我们最近发现，棕色脂肪组织释放的代谢物信号可以激活白色脂肪组织中的米色细胞，并导致肌肉组织燃烧脂肪。这些代谢物具有抗肥胖的特性，突出了代谢物在组织之间传递信号以影响能量平衡的机制。这一建议建立在我们的发现的基础上，研究白色脂肪组织的褐变是否会导致一种也具有信号特性的脂肪分子(称为脂肪因子)的释放。这种脂肪因子在邻近的白色脂肪组织中诱导褐变并进入血液，向肝脏和肌肉等其他器官发出改变其代谢特征的信号的能力将被调查。这项研究将确定米色细胞特有的脂肪因子信号，脂肪细胞产生和释放脂肪因子信号的方式，以及这种脂肪因子在人类肥胖中的重要性。脂肪因子将被评估其改善代谢健康和预防肥胖的能力。这项研究将加深我们对脂肪组织如何与肝脏和肌肉等其他组织在调节全身能量平衡方面的沟通的理解，并有助于确定其在肥胖发生中的作用。这些研究中发现的新的米色脂肪信号可能被证明是对全球肥胖症流行有用的治疗方法，或者突出新的治疗目标，从而有助于抗肥胖药的开发。这项研究将通过识别脂肪组织和其他器官之间的新信号来突出进一步研究的领域，这些信号可能通过它们的活动或破坏而导致代谢性疾病。这项拟议的研究可能有助于预防代谢性疾病；由于我们饮食中发现的许多脂肪与体内发现的脂肪重叠，识别具有有益代谢作用的脂素可能有助于指导健康的饮食选择。

Obesity is characterised by high levels of body fat leading to a body mass index of over 30. Over 650 million people worldwide are living with obesity. Obesity increases the risk of cardiovascular disease, some cancers and type 2 diabetes (T2D). Given the number of people affected, the impact on their quality of life and the burden on healthcare, finding new treatments is essential.Energy balance is a key concept behind our understanding of metabolism and metabolic diseases like obesity. The balance between energy uptake (food intake), and energy expenditure (everyday biological processes / physical activity) determines whether a person is lean or obese. A chronic imbalance in energy, with excess uptake in combination with reduced expenditure, leads to increased storage of energy as fats within white fat cells in white fat tissue and can lead to metabolic diseases including obesity and T2D.Many biological processes relevant to the development or treatment of obesity involve fat tissue. White fat tissue, once considered only as an energy-storage depot, is now known to be the source of key biological signals, known as adipokines, which are released into the blood and communicate to other organs to regulate whole-body metabolism. Not all fat cells are the same, however. A second group of fat cells, known as brown fat cells, regulate body temperature by "burning" stored fats to produce heat. A third group, known as beige fat cells, can switch from behaving like a white fat cell (storing fat) to functioning like a brown fat cell (burning fat), in a process known as "browning". In humans, beige fat makes up the majority of this heat producing tissue but is also found within white fat tissue and once activated has anti-obesity effects. Recent studies, including our own, suggest several of the anti-obesity properties of beige fat may occur by non-heat producing effects through the release of signals into the blood which communicate with other tissues such as the liver and muscle to alter their metabolism. We recently discovered metabolite signals released from browning adipose tissue that activate beige cells in white fat tissue and cause muscle tissue to burn fat. The metabolites had anti-obesity properties, highlighting a mechanism in which metabolites signal between tissues to influence energy balance.This proposal builds on our findings by investigating whether browning of white fat tissue results in the release of a type of fat molecule that also has signalling properties (known as a lipokine). The capacity of this lipokine to induce browning in areas of neighbouring white fat tissue and to enter into the blood, signalling to other organs such as the liver and muscle to change their metabolic characteristics, will be investigated. This research will identify beige cell-specific lipokine signals, the way in which fat cells produce and release the lipokine signal, and the importance of this lipokine in human obesity. The lipokine will be evaluated for its capacity to improve metabolic health and protect against obesity.This research will improve our understanding of how fat tissue communicates with other tissues such as liver and muscle in regulating whole-body energy balance, and help to define its contribution to obesity development. Novel beige fat signals identified in these studies may prove to be useful treatments for the global obesity epidemic, or highlight new treatment targets and so contribute to anti-obesity drug development. This study will highlight areas of further research by identifying novel signals communicating between fat tissue and other organs that may contribute, through their activity or disruption, to metabolic disease. The proposed research may contribute to prevention of metabolic disease; since many fats found within our diets overlap with those found within the body, the identification of lipokines with beneficial metabolic effects may help inform healthy dietary choices.