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.

项目概要 在美国和世界各地，肥胖率正在稳步上升，这是一个重大的健康问题 肥胖与糖尿病和心脏病等多种主要死亡原因有关。 减肥通常极具挑战性，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 来自代谢机制，是能量消耗的组成部分之一。之前的研究有 研究表明，生热作用减少会导致脂肪和体重增加，而生热作用增加则会促进脂肪和体重增加。 体重和脂肪减少。因此，刺激适应性产热代表了一种有前途的治疗方法 肥胖流行病。然而，目前的研究途径尚未确定一个产热目标 可用于有效促进减肥。钠/碘同向转运体 (NIS) 是关键的等离子体 介导碘依赖钠依赖性主动转运至甲状腺滤泡的膜蛋白 细胞，甲状腺激素（TH）生物合成的第一步。我们开发了一种无药物模型 通过将小鼠置于严重甲状腺功能减退症（无法检测到 TH 和促甲状腺激素；TSH 增加） 这是低碘饮食中 NIS 的淘汰赛。尽管体力活动减少，这些小鼠体重却没有增加 与轻度甲状腺功能减退症模型（低碘化物野生型小鼠）相比，食物摄入量水平相似 饮食）。此外，严重甲状腺功能减退小鼠的骨骼标志物表达显着增加。 肌肉适应性产热和增加骨骼肌 O2 消耗。在这些基础上 初步结果，我假设骨骼肌的适应性生热作用是 在严重甲状腺功能减退的情况下受到刺激，防止体重增加。为了测试这个 假设，我将测量甲状腺功能正常的对照小鼠的生热作用，并确定其身体成分 以及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，均使用 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 将使我能够区分 TH 减少对适应性产热的影响和 促甲状腺激素升高。骨骼肌原代培养物、肌浆网囊泡的转运测定、 甲状腺功能正常的 TSH-R KO 小鼠将用于最终证明骨骼肌生热作用 当 TH 减少时会受到刺激（c 部分）。将进行体外研究以确定其机制 负责甲状腺功能减退引起的骨骼肌产热（d 部分）。下丘脑的作用—— 骨骼肌产热和甲状腺功能减退引起的产热中的垂体-甲状腺轴都是 产热研究在很大程度上尚未探索，因此将使我们能够确定新的减肥目标 这可用于对抗肥胖流行病。