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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要在美国和世界各地，肥胖率正在稳步上升，这是一个主要的健康状况肥胖症的关注与包括糖尿病和心脏病在内的多种主要死亡原因有关。减肥通常极具挑战性，因为我们的身体自然会减少能源消耗减肥。自适应生热发生是通过产生热量维持体温的可持续方法来自代谢机制，是能量消耗的组成部分之一。先前的研究已有表明减少的热发生会导致脂肪和体重增加，而增加的热发生促进体重和脂肪减少。因此，刺激自适应生热作用是一种有前途的治疗方法肥胖流行。但是，目前的研究途径尚未确定一个热目标可用于有效促进体重减轻。钠/碘化物分类器（NIS）是关键等离子体膜蛋白介导碘化物钠依赖的活性转运到甲状腺卵泡细胞，甲状腺激素（THS）生物合成的第一步。我们已经开发了一个无药模型的通过放置小鼠，严重的甲状腺功能减退症（无法检测到的THS和增加甲状腺刺激激素； TSH）这是低碘化物饮食中NIS的淘汰赛。尽管体育锻炼减少了，这些老鼠仍无法增加体重与轻度甲状腺功能减退症模型相比（低碘化物上的野生型小鼠饮食）。另外，严重甲状腺功能低下的小鼠显着增加了骨骼标记的表达肌肉自适应生热作用和骨骼肌O2消耗量增加。根据这些初步结果，我假设骨骼肌中的自适应生热为在严重甲状腺功能减退症的条件下刺激，防止体重增加。测试这个假设，我将测量热生成并确定甲状腺控制小鼠的身体组成和两种不同种类的严重甲状腺功能低下小鼠：NIS KO和TSH受体（TSH-R）KO小鼠，都在A上低碘化物饮食（A部分和B）。重要的是，使用这两种不同的严重甲状腺功能减退症的小鼠模型将使我能够区分降低TH对自适应热发生的影响和增加TSH。骨骼肌原发性培养物，肌质网中的运输测定法，和甲状腺甲状腺TSH-R KO小鼠将最终证明骨骼肌的热发生是当Ths降低时刺激（C部分）。将进行体外研究以确定机制负责甲状腺功能减退症引起的骨骼肌热发生（D部分）。下丘脑的作用骨骼肌热发生和甲状腺功能减退症引起的垂体 - 甲状腺轴都是在很大程度上未开发的热研究领域，因此，我们可以识别新的减肥目标可以用来对抗肥胖流行。