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：
10453744
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453744
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 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 wireless

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) 是一种产热脂肪细胞（棕色和米色脂肪）特有的线粒体蛋白，可解偶联细胞呼吸和线粒体 ATP 合成，以热量形式耗散能量，因为 UCP1 被认为是唯一负责非产热的蛋白。关于脂肪组织中的颤抖产热，普遍的观点是 UCP1 的作用主要介导棕色和米色脂肪的功能，从而促进然而，我们之前的资助周期和其他实验室的数据表明，棕色/米色脂肪缺乏和 UCP1 缺乏之间的代谢表型不一致：我们发现米色脂肪缺乏的小鼠。由 PRDM16 或其辅助因子 EHMT1 的脂肪特异性缺失引起，即使在环境温度下也会出现肥胖和葡萄糖不耐症，而 UCP1 敲除小鼠则不会患糖尿病并出现肥胖这种差异促使我们寻找不依赖于 UCP1 的能量稳态调节机制，我们最近发现了一种非规范的（不依赖于 UCP1 的）产热机制，它可以解释上述不依赖于 UCP1 的生热机制。通过 Sarco/内质网 Ca2+-ATPase2b (SERCA2b) 和 Ryanodine 受体 2 进行依赖的 Ca2+ 循环米色脂肪中的 Ca2+ 循环热生成部分通过响应冷刺激的 α1-AR 信号被激活，并且需要活跃的葡萄糖氧化，从而米色脂肪起到“葡萄糖汇”的作用并改善全身葡萄糖耐量。值得注意的是，Ca2+ 循环生热作用是人类、小鼠以及猪（一种缺乏功能性 UCP1 蛋白的稀有哺乳动物）中进化上保守的机制。确定米色脂肪中这种非典型生热作用的生物学意义和机制。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis.

人类的棕色和米色脂肪：控制能量和葡萄糖稳态的产热脂肪细胞。

DOI：
10.1172/jci78362
发表时间：
2015-02-02
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
L. Sidossis;S. Kajimura
通讯作者：
S. Kajimura

Lightening up a notch: Notch regulation of energy metabolism.

减轻一个档次：能量代谢的档次调节。

DOI：
发表时间：
2014-08
期刊：
影响因子：
82.9
作者：
Gridley, Thomas;Kajimura, Shingo
通讯作者：
Kajimura, Shingo

Relevance of brown adipose tissue in infancy and adolescence.

婴儿期和青春期棕色脂肪组织的相关性。

DOI：
发表时间：
2013-01
期刊：
影响因子：
3.6
作者：
Gilsanz, Vicente;Hu, Houchun H;Kajimura, Shingo
通讯作者：
Kajimura, Shingo

Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis.

人白色脂肪细胞中的线粒体活性由泛素载体蛋白 9/microRNA-30a 轴调节。

DOI：
发表时间：
2016-11-18
期刊：
影响因子：
0
作者：
Koh, Eun Hee;Chen, Yong;Bader, David A;Hamilton, Mark P;He, Bin;York, Brian;Kajimura, Shingo;McGuire, Sean E;Hartig, Sean M
通讯作者：
Hartig, Sean M

Regulation of systemic energy homeostasis by serotonin in adipose tissues.

脂肪组织中血清素调节全身能量稳态。

DOI：
发表时间：
2015-04-13
期刊：
影响因子：
16.6
作者：
Oh, Chang;Namkung, Jun;Go, Younghoon;Shong, Ko Eun;Kim, Kyuho;Kim, Hyeongseok;Park, Bo;Lee, Ho Won;Jeon, Yong Hyun;Song, Junghan;Shong, Minho;Yadav, Vijay K;Karsenty, Gerard;Kajimura, Shingo;Lee, In;Park, Sangkyu;Kim, Hail
通讯作者：
Kim, Hail