Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

棕色脂肪细胞命运和能量代谢的分子控制

基本信息

批准号：
10210322
负责人：
Shingo Kajimura
金额：
$ 49.56万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210322
关键词：
ATP Synthesis Pathway Address Adipocytes Adipose tissue Adrenergic Receptor Antidiabetic Drugs Binding Bioenergetics Biological Cell Respiration Cues Data Devices Diabetes Mellitus Disease Elderly Endoplasmic Reticulum Energy Metabolism Evolution Family suidae Fatty acid glycerol esters Funding Glucose Glucose Intolerance Health Homeostasis Human Knockout Mice Lead Mediating Medicine Metabolic Diseases Mitochondria Mitochondrial Proteins Molecular Monitor Mus Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Pathologic Physiological Physiology Population Proteins Publishing Regulation Reporter Ryanodine Receptor Calcium Release Channel Signal Transduction Stimulus System Temperature Testing Therapeutic Intervention Thermogenesis Transmembrane Domain Wireless Technology blood glucose regulation diabetic diet-induced obesity glucose tolerance improved in vivo innovation loss of function metabolic phenotype obesity treatment optogenetics oxidation response spatiotemporal subcutaneous therapeutically effective uncoupling protein 1

项目摘要

Uncoupling Protein 1 (UCP1) is a mitochondrial protein specific to thermogenic adipocytes (brown and beige fat) that uncouples cellular respiration and mitochondrial ATP synthesis to dissipate energy in the form of heat. Because UCP1 has been considered the sole thermogenic protein responsible for non-shivering thermogenesis in the adipose tissue, the prevailing dogma is that the action of UCP1 primarily mediates the functions of brown and beige fat, which promote the anti-obesity and anti-diabetic effects when activated. However, our data from the previous funding cycle and other labs suggest an incongruity in the metabolic phenotypes between brown/beige fat-deficiency and UCP1-deficiency: we found that beige fat-deficient mice, caused by the fat-specific deletion of PRDM16 or its co-factor EHMT1, develop obesity and glucose intolerance even under ambient temperature, whereas UCP1 knockout mice are not diabetic and develop obesity only under thermoneutrality. This discrepancy motivated us to search for UCP1-independent mechanisms in the regulation of energy homeostasis. We recently identified a non-canonical (UCP1-independent) thermogenic mechanism that may explain the above quandary. UCP1-independent thermogenesis involves ATP-dependent Ca2+ cycling through Sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b) and Ryanodine Receptor 2 (RyR2) in beige fat. Ca2+ cycling thermogenesis is activated, in part, through α1-AR signaling in response to a cold stimulus, and requires active glucose oxidation. Thereby beige fat functions as a “glucose sink” and improves systemic glucose tolerance. Notably, Ca2+ cycling thermogenesis is an evolutionally conserved mechanism in humans, mice, and also in pigs, a rare mammalian species that lacks a functional UCP1 protein. Accordingly, the current proposal aims to determine the biological significance and the mechanisms pertinent to this non-canonical thermogenesis in beige fat.

解偶联蛋白1（UCP1）是一种针对热脂肪细胞（棕色和米色脂肪）的线粒体蛋白，它取消了细胞呼吸和线粒体ATP合成，以热的形式散发能量。由于UCP1被认为是负责脂肪组织中不动热量的唯一热蛋白，因此，流行的教条是UCP1主要的作用介导了棕色和米色脂肪的功能，这些功能会促进抗肥胖和抗饮食效应。 However, our data from the previous foundation cycle and other labs suggest an incongruity in the metabolic phenotypes between brown/beige fat-deficiency and UCP1-deficiency: we found that fat-deficiency mice, caused by the fat-specific deletion of PRDM16 or its co-factor EHMT1, developing obesity and glucose intlerance even under ambient temperature, whereas UCP1 knockout mice are Not糖尿病和仅在热自治下发展肥胖。这种差异促使我们在调节能量稳态的调节中寻找独立于UCP1的机制。我们最近确定了一种非典型（UCP1独立的）热机制，该机制可能解释了上述量子。 UCP1非依赖性的热发生涉及依赖于ATP的Ca2+循环通过sarco/内质网Ca2+ -atpase2b（SERCA2B）（SERCA2B）和ryanodine受体2（RYR2）中的ATP循环。 Ca2+循环热发生部分通过响应冷刺激而通过α1-AR信号传导激活，并需要活跃的葡萄糖氧化。因此，米色脂肪作为“葡萄糖下水道”的功能，并提高系统性葡萄糖耐受性。值得注意的是，Ca2+循环热发生是人类，小鼠以及猪的一种进化配置的机制，这是一种缺乏功能性UCP1蛋白的罕见哺乳动物物种。彼此之间，当前的提案旨在确定与米色脂肪中这种非经典热发生有关的生物学和机制。