The Role Of Thyroid Hormone Receptor Signaling In White Adipose Tissue Mediated Adaptive Thermogenesis

 描述(申请人提供)：肥胖是一种加速的国民健康危机，它与各种共病有关，通常被称为代谢综合征。由于肥胖是由长期摄入过量能量引起的，因此抗肥胖疗法必须减少能量摄入或增加能量输出。一种有趣的增加能量消耗的可能性是利用适应性产热的力量来提高代谢率。通过将呼吸作用从ATP合成中分离出来，适应性生热作用能够将多余的能量(如多余的卡路里)直接转化为热量。我们非常感激， 甲状腺激素和激素受体与产热有关，尽管这种关系的机制基础尚不清楚。在进行旨在阐明甲状腺激素信号和产热之间机制关系的长期研究时，人们发现了一种合成的促甲状腺激素受体激动剂，它通过显著诱导白色脂肪组织(WAT)内的适应性产热和非耦合呼吸程序而产生显著的抗肥胖效果，这种效果被称为“褐变”。激素受体激动剂诱导的WAT褐变还伴随着几种有益的效果，这些效果反对肥胖和代谢综合征。这些结果清楚地表明，药理上的TR激活可以赋予Wat类似棕色脂肪的功能，并引发了与这一作用相关的几个问题：“Wat棕色是不是对TR激动剂的有益代谢效应(如脂肪减少、胰岛素敏感性改善、血清甘油三酯降低)负责？” 这一现象在治疗代谢性疾病中的潜在用途。“Wat褐变是否代表了甲状腺激素过量引起‘甲状腺产热’的机制？”最后，“tr的激活导致适应性产热的完整遗传程序的诱导的机制是什么？”本研究的目的是为了从以下两个方面回答上述问题：1)确定受体激动剂诱导Wat褐变的药理和生理意义；2)确定TrR激活导致Wat褐变的分子机制。实现第一个目标的方法是使用不同小鼠品系的功能丧失方法来精确定义BAT和WAT中的适应性产热作用在多大程度上有助于在TR激活后看到的全身效应。第二个目标是利用在体外诱导褐变的能力，以研究在细胞培养中TRR激动剂引起这种作用的机制基础。

 DESCRIPTION (provided by applicant): Obesity is an accelerating national health crisis which is associated with a variety of comorbidities, often referred to as metabolic syndrome. As obesity is caused by a chronic intake of excess energy, anti-obesity therapies must either decrease energy intake or increase energy output. An intriguing possibility to increase energy expenditure has been to harness the power of adaptive thermogenesis to increase metabolic rate. By uncoupling respiration from ATP synthesis, adaptive thermogenesis enables the conversion of excess energy (such as excess calories) directly to heat. It is well appreciated that thyroid hormone and the TRs are associated with thermogenesis, although the mechanistic basis for this relationship is not clear. While conducting long-term studies aimed at elucidating the mechanistic relationship between thyroid hormone signaling and thermogenesis, a synthetic TR agonist was discovered that elicits substantial anti-obesity effects by markedly inducing a program of adaptive thermogenesis and uncoupled respiration within white adipose tissue (WAT), an effect that has come to be known as 'browning'. TR agonist induced browning of WAT is also accompanied by several beneficial effects that oppose obesity and metabolic syndrome. These results make it clear that pharmacological TR activation can impart brown fat-like function upon WAT and prompts several questions related to this action: "Is WAT browning responsible for the beneficial metabolic effects of the TR agonist (such as fat loss, improved insulin sensitivity, decreased serum triglycerides)?", a question that has obvious implications for the potential of this phenomenon to be used therapeutically in the treatment of metabolic disease. "Does WAT browning represent the mechanism by which thyroid hormone excess elicits 'thyroid thermogenesis'"? And finally, "What is the mechanism by which TR activation leads to induction of the full genetic program of adaptive thermogenesis?" The purpose of this proposal is to answer the aforementioned questions within the following 2 major aims: 1) To determine the pharmacological and physiological significance of TR agonist induced WAT browning and 2) To determine the molecular mechanism by which TR activation leads to the browning of WAT. The approach to the first aim is to use loss of function approach with various mouse lines to define precisely how much adaptive thermogenesis in both BAT and WAT contribute to the systemic effects seen subsequent to TR activation. The approach to the second aim is to exploit the ability to induce browning in vitro to study the mechanistic basis by which TR agonism elicits this action in cell culture.