Molecular Regulation of Beige Fat Cells in Mice and Humans

描述（由申请人提供）：该提案要求为Jun Wu的K 01的最后两年提供额外资金，并促进她过渡到代谢研究的独立研究者。与肥胖相关的深远的健康后果强调了开发有效的治疗干预措施的重要性。肥胖本质上是一种能量平衡紊乱，摄入超过支出。广义上，脂肪细胞分为白色和棕色脂肪细胞。白色脂肪细胞专门用于储存化学能，而棕色脂肪通过线粒体解偶联蛋白1（UCP 1）介导的产热来抵御体温过低和肥胖。资助的K奖导致了从小鼠白色脂肪库中分离出米色细胞。与来自myf-5+肌肉样细胞谱系的经典棕色脂肪不同，分散在白色脂肪组织中的米色脂肪细胞来自非myf-5谱系。米色细胞的基因表达模式与白色或棕色脂肪不同。米色细胞类似于白色脂肪细胞，具有极低的Ucp 1基础表达，但像经典的棕色脂肪，它们响应于环AMP刺激，具有高Ucp 1表达和呼吸速率。原代米色脂肪细胞优先对多肽激素鸢尾素敏感，其诱导白色脂肪库的“布朗宁”并改善葡萄糖稳态。先前在成年人中观察到的UCP-1+脂肪细胞的沉积物在分子上与鼠米色脂肪细胞比棕色脂肪细胞更接近。该提案的总体目标是通过米色选择性标记和激素反应研究米色脂肪的分子调控;以及米色脂肪如何影响人类的系统代谢稳态。目标1。先前的研究表明，米色标记物CD 137的激活会增加啮齿动物的能量消耗，但其机制尚不清楚。将在体外和体内研究CD 137活化/失活如何影响米色脂肪功能。目标2。将研究已知诱导白色脂肪库“布朗宁”的分子，以了解它们如何影响米色脂肪细胞功能的分子机制。米色选择性激素/信号分子将被确定和功能特征。将进行基因集富集分析，以说明米色选择性激素应答的下游信号级联。目标3。初步数据显示，在来自各种人类脂肪库的初级基质血管部分（SVF）的分化培养物中，在鸢尾素处理后产热程序的稳健上调，表明米色前体/脂肪细胞可能存在于人类的这些脂肪库中。将使用已建立的米色细胞分选方案从锁骨上区域和皮下脂肪组织（抽脂样品）中分离初级米色前体，并研究人米色脂肪功能。

DESCRIPTION (provided by applicant): This proposal requests additional funding for the last two-year period of Jun Wu's K01 and to facilitate her transition into an independent investigator in metabolic research. The profound health consequences associated with obesity emphasize the importance of developing effective therapeutic interventions. Obesity is essentially a disorder of energy balance, in which intake exceeds expenditure. Broadly, adipocytes have been divided into white and brown fat cells. White fat cells are specialized to store chemical energy, whereas brown fat defends against hypothermia and obesity through thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). The funded K award has led to the isolation of beige cells from murine white fat depots. Different from the classical brown fat, whic is derived from a myf-5+ muscle-like cellular lineage, beige fat cells, dispersing in white fat tissues are from a non-myf-5 lineage. Beige cells have a gene expression pattern distinct from either white or brown fat. Beige cells resemble white fat cells in having extremely low basal expression of Ucp1, but like classical brown fat, they respond to cyclic AMP stimulation with high Ucp1 expression and respiration rates. Primary beige adipocytes are preferentially sensitive to the polypeptide hormone irisin, which induces "browning" of the white adipose depots and improves glucose homeostasis. Deposits of UCP-1+ adipocytes previously observed in adult humans molecularly resemble murine beige adipose cells much more closely than brown. The overall goal of this proposal is to study molecular regulation of beige fat through beige-selective markers and hormonal responses; and how beige fat impacts systematic metabolic homeostasis in humans. Aim #1. Previous studies shown that activation of beige marker CD137 will increase energy expenditure in rodents, but the mechanism is unknown. How CD137 activation/inactivation affects beige fat function will be investigated in vitro and in vivo. Aim #2. Molecules known to induce "browning" of the white fat depots will be investigated for the molecular mechanisms how they affect beige adipocytes function. Beige-selective hormones/signaling molecules will be identified and functionally characterized. Gene set enrichment analysis will be conducted to illustrate downstream signaling cascades of beige selective hormonal response(s). Aim #3. Preliminary data shown a robust upregulation of thermogenic program upon irisin treatment in the differentiated cultures of primary stromal vascular fraction (SVF) from various human adipose depots, suggesting that beige precursors/adipocytes may exist in these adipose depots in humans. Primary beige precursors will be isolated from both supraclavicular region and subcutaneous adipose tissues (liposuction samples) using the established beige cell sorting protocols and human beige fat functions will be investigated.