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

甲状腺激素受体信号在白色脂肪组织介导的适应性产热中的作用

• 批准号: 9136146
• 负责人: Kevin John Phillips
• 金额: $ 15.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-02 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136146
• 关键词: ATP Synthesis Pathway; Adipocytes; Adipose tissue; Agonist; Body Weight decreased; Brown Fat; Burn injury; Calories; Cell Culture Techniques; Chronic; Comorbidity; Denervation; Disease; Energy Intake; Energy Metabolism; Fatty acid glycerol esters; GC 1 compound; Genetic Programming; Health; Heating; Hyperthermia; Hyperthyroidism; Hypertriglyceridemia; In Vitro; Insulin Resistance; Intake; Ligands; Lipids; Longitudinal Studies; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Molecular; Morphology; Mus; Obesity; Output; Physiological; Receptor Activation; Receptor Signaling; Respiration; Role; Serum; Signal Transduction; Source; Thermogenesis; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Triglycerides; Weight Gain; base; improved; insulin sensitivity; loss of function; metabolic rate; programs; receptor; subcutaneous

 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.

 描述（由适用提供）：肥胖是一种加速的国家健康危机，与多种合并症有关，通常称为代谢综合征。由于肥胖是由于慢性摄入过量能量引起的，因此抗肥胖疗法必须降低能量摄入量或增加能量输出。增加能量消耗的一种有趣的可能性是利用适应性热发生以提高代谢率的力量。通过解开ATP合成的呼吸，自适应热发生使多余能量（例如过量卡路里）的转化为热。非常感谢 尽管这种关系的机械基础尚不清楚，但甲状腺龙骨和TRS与热发生有关。在进行长期研究旨在阐明甲状腺鸡蛋子信号传导和热生成之间的机械关系时，发现合成的TR激动剂是发现，通过明显诱导了适应性热生成和无偶联的抗肥胖效应，从而引发了实质性的抗肥胖效应，并在白色脂肪组织（WAT）中引起了无知的效果，这一效果是众所周知的。 Tr动力学诱导的WAT呈褐变也是通过反对肥胖和代谢综合征的几种有益作用来完成的。这些结果清楚地表明，药物TR激活可以在WAT上赋予棕色脂肪样的功能，并提示与此动作有关的几个问题：“ WAT褐变是否负责TR激动剂的有益代谢作用（例如脂肪损失，改善胰岛素敏感性，改善血清甘油三酸酯）？” 这种现象的潜力用于治疗代谢疾病。 “水褐变是否代表甲状腺多余的甲状腺热生成的机制”？最后，“ TR激活导致适应性热生成的完整遗传程序的机制是什么？”该提案的目的是在以下两个主要目的中回答优先问题：1）确定Tr激动剂诱导的Wat Browning的药理和物理意义和2）确定TR激活导致WAT褐变的分子机制。第一个目的的方法是使用各种小鼠系使用功能方法的丧失，以精确定义BAT和WAT中的自适应热发生，从而有助于TR激活后看到的全身效应。第二种目的的方法是利用体外诱导褐变的能力，以研究Tr agonism在细胞培养中引起这种作用的机械基础。