Novel insights into the role of the hypothalamic-pituitary-thyroid axis in skeletal muscle adaptive thermogenesis

关于下丘脑-垂体-甲状腺轴在骨骼肌适应性产热中作用的新见解

• 批准号: 9756508
• 负责人: Rachel Kaspari
• 金额: $ 4.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756508
• 关键词: ATP Hydrolysis; Active Biological Transport; Address; Adipose tissue; Adult; Anabolism; Animal Model; Area; Attention; Biological Assay; Blood Circulation; Body Composition; Body Temperature; Body Weight decreased; Ca(2+)-Transporting ATPase; Cause of Death; Cell membrane; Cells; Clinical; Consumption; Diabetes Mellitus; Diet; Eating; Endoplasmic Reticulum; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Feedback; Fluorescent Dyes; Fura-2; Futile Cycling; Goals; Health; Heart Diseases; Human; Hypothyroidism; In Vitro; Intervention; Iodides; Iodine; Knockout Mice; Lead; Malignant Neoplasms; Measures; Mediating; Membrane Proteins; Metabolic; Modeling; Mus; Myocardium; Obesity; Obesity Epidemic; Pharmaceutical Preparations; Pharmacology; Physical activity; Proteolipids; Pump; Regulation; Research; Role; SLC5A5 gene; Sarcoplasmic Reticulum; Skeletal Muscle; Sodium; Sympathetic Nervous System; Testing; Thermogenesis; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin Receptor; United States; Vesicle; Weight; Weight Gain; Wild Type Mouse; Work; combat; effective therapy; experimental group; experimental study; hormone biosynthesis; hypothalamic-pituitary-thyroid axis; insight; mRNA Transcript Degradation; mouse model; muscle form; novel; prevent; promoter; protein degradation; ratiometric; response; sarcolipin; virtual

PROJECT SUMMARY The rate of obesity is steadily increasing in the United States and around the world, which is a major health concern as obesity is associated with multiple leading causes of death including diabetes and heart disease. Losing weight is often extremely challenging as our bodies naturally reduce energy expenditure in response to weight loss. Adaptive thermogenesis is a sustainable way to maintain body temperature by generating heat from metabolic mechanisms and is one of the components of energy expenditure. Previous studies have shown that reduced thermogenesis causes fat and weight gain, while increased thermogenesis promotes weight and fat loss. Therefore, stimulating adaptive thermogenesis represents a promising approach to treat the obesity epidemic. However, current avenues of research have yet to identify a thermogenic target that could be used to efficaciously promote weight loss. The sodium/iodide symporter (NIS) is the key plasma membrane protein that mediates the sodium-dependent active transport of iodide into the thyroid follicular cells, the first step in the biosynthesis of the thyroid hormones (THs). We have developed a drug-free model of severe hypothyroidism (undetectable THs and increased thyroid-stimulating hormone; TSH) by placing mice that are knockouts for NIS on a low iodide diet. These mice fail to gain weight despite reduced physical activity and similar levels of food intake compared to a model of mild hypothyroidism (wild-type mice on a low iodide diet). In addition, severely hypothyroid mice exhibit significantly increased expression of markers of skeletal muscle adaptive thermogenesis and increased skeletal muscle O2 consumption. On the basis of these preliminary results, I hypothesize that adaptive thermogenesis in the skeletal muscle is stimulated under conditions of severe hypothyroidism, preventing weight gain. To test this hypothesis, I will measure thermogenesis in, and determine the body composition of, euthyroid control mice and two different kinds of severely hypothyroid mice: NIS KO and TSH receptor (TSH-R) KO mice, both on a low-iodide diet (Part a and b). Importantly, using these two different mouse models of severe hypothyroidism will allow me to differentiate between the effects of reduced THs on adaptive thermogenesis and those of increased TSH. Skeletal muscle primary cultures, transport assays in sarcoplasmic reticulum vesicles, and euthyroid TSH-R KO mice will be used to conclusively show that skeletal muscle thermogenesis is stimulated when THs are reduced (Part c). In vitro studies will be performed to determine the mechanisms responsible for hypothyroidism-induced skeletal muscle thermogenesis (Part d). The role of the hypothalamic- pituitary-thyroid axis in skeletal muscle thermogenesis and hypothyroidism-induced thermogenesis are both largely unexplored areas of thermogenic research, and as such will allow us to identify new weight-loss targets that may be used to combat the obesity epidemic.

项目摘要 肥胖率在美国和世界各地都在稳步上升，这是一个主要的健康问题。 肥胖与包括糖尿病和心脏病在内的多种主要死亡原因有关。 减肥通常是非常具有挑战性的，因为我们的身体会自然地减少能量消耗，以应对 减肥.适应性产热是一种通过产生热量来维持体温的可持续方式 从代谢机制，是能量消耗的组成部分之一。先前的研究 表明减少产热导致脂肪和体重增加，而增加产热促进 体重和脂肪损失。因此，刺激适应性产热是一种有前途的治疗方法。 肥胖症的流行然而，目前的研究途径尚未确定一种产热靶点， 可以有效地促进减肥。钠/碘同向转运体（NIS）是关键的血浆 一种介导碘离子向甲状腺滤泡内的钠依赖性主动转运的膜蛋白 甲状腺激素（TH）是甲状腺激素合成的第一步。我们开发了一种无药物模型， 严重的甲状腺功能减退症（检测不到TH和增加促甲状腺激素; TSH）， 在低碘饮食中敲除NIS。这些小鼠尽管减少了体力活动， 并且与轻度甲状腺功能减退症模型（低碘化物的野生型小鼠）相比， 饮食）。此外，严重甲状腺功能减退的小鼠表现出骨骼肌标志物的表达显著增加， 肌肉适应性产热和增加骨骼肌O2消耗。根据这些 根据初步结果，我假设骨骼肌中的适应性产热是 在严重甲状腺功能减退的情况下刺激，防止体重增加。为了验证这一 假设，我将测量产热，并确定身体组成，甲状腺功能正常的对照小鼠 和两种不同类型的严重甲状腺功能减退小鼠：NIS KO和TSH受体（TSH-R）KO小鼠，两者均在一个 低碘饮食（a和B部分）。重要的是，使用这两种不同的严重甲状腺功能减退症小鼠模型， 这将使我能够区分减少TH对适应性产热的影响和减少TH对适应性产热的影响。 TSH升高骨骼肌原代培养，肌浆网囊泡转运试验， 和甲状腺功能正常的TSH-R基因敲除小鼠将被用于最终证明骨骼肌产热是 当TH减少时刺激（部分c）。将进行体外研究以确定其机制 负责甲状腺功能减退症诱导的骨骼肌产热（d部分）。下丘脑的作用- 垂体-甲状腺轴在骨骼肌产热和甲状腺功能减退症引起的产热中的作用都是 这是生热研究中尚未探索的领域，因此将使我们能够确定新的减肥目标。 可以用来对抗肥胖症的流行。