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

 描述（由申请人提供）：肥胖是一种加速的国家健康危机，与多种合并症相关，通常称为代谢综合征。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。增加能量消耗的一个有趣的可能性是利用适应性产热的力量来增加代谢率。通过将呼吸与ATP合成分离，适应性产热能够将多余的能量（如多余的卡路里）直接转化为热量。值得赞赏的是， 甲状腺激素和TRs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传导和产热之间的机制关系的长期研究时，发现合成的TR激动剂通过显著诱导白色脂肪组织（WAT）内的适应性产热和非偶联呼吸的程序来增强显著的抗肥胖效果，该效果被称为“褐变”。TR激动剂诱导的WAT的布朗宁还伴随着对抗肥胖和代谢综合征的几种有益效果。这些结果清楚地表明，药理学TR激活可以赋予WAT棕色脂肪样功能，并提示了与此作用相关的几个问题：“WAT布朗宁是否是TR激动剂的有益代谢作用（如脂肪损失、改善胰岛素敏感性、降低血清甘油三酯）的原因？“，这个问题对 这种现象在治疗代谢性疾病中的潜在用途。“WAT布朗宁是否代表甲状腺激素过量导致”甲状腺产热“的机制”？最后，“TR激活导致诱导适应性产热的完整遗传程序的机制是什么？“本提案的目的是在以下两个主要目标内回答上述问题：1）确定TR激动剂诱导WAT布朗宁的药理学和生理学意义; 2）确定TR激活导致WAT布朗宁的分子机制。第一个目标的方法是使用各种小鼠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对TR激活后观察到的全身效应有多大贡献。第二个目的的方法是利用诱导布朗宁的能力，在体外研究的机制基础，TR激动elavenous这一行动在细胞培养。

 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.