CD47 as a therapeutic target for obesity

棕色脂肪组织(BAT)通过UCP1介导的非偶联呼吸及其激活来消耗能量 可能代表了一种对抗肥胖的治疗策略。初步研究确定了CD47的一个新作用 在调节BAT功能及其对能量平衡和肥胖发展的贡献方面。 CD47是一种普遍表达的细胞膜受体，与自我识别和免疫功能有关。 在肥胖动物的脂肪组织中表达上调。此外，CD47缺乏保护了小鼠的饮食- 通过激活BAT功能(如增强线粒体解偶联和加热)诱导肥胖(DIO) 生产)和增加能源消耗。这些数据表明CD47是BAT的负性调节因子 活动。因此，抑制CD47信号可能是一种新的减肥策略，这进一步 由最近的一项人类全基因组研究支持，该研究表明单核苷酸多态之间存在关联 CD47基因与体重、体重指数的关系。在这项提案中，CD47下调监管的机制 棕色脂肪细胞的功能将在目标1中确定。棕色脂肪细胞特异性CD47的贡献 肥胖发展的缺陷将在目标2中确定。CD47是否抑制CD47信号- 反义寡核苷酸(ASO)治疗激活BAT并预防/改善动物肥胖 模型将在目标3中确定。这些研究不仅将提供有关机制的新信息 CD47通过下调棕色脂肪功能及其对能量动态平衡的贡献 肥胖的发展，也测试了CD47-ASO在肥胖小鼠模型中的抗肥胖潜力。 因此，这些研究具有临床意义。

Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47 in regulating BAT function and its contribution to energy homeostasis and the development of obesity. CD47, a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune function, was upregulated in adipose tissue from obese animals. Moreover, CD47 deficiency protected mice from diet- induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heat production) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BAT activity. Therefore, inhibition of CD47 signaling might be a novel anti-obesity strategy, which is further supported by a recent human genome-wide study showing the association of single-nucleotide polymorphisms in CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulates brown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47 deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47- antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animal models will be determined in Aim 3. These studies will not only provide novel information on the mechanisms by which CD47 down-regulates brown fat function and its contribution to energy homeostasis and the development of obesity, but also test the anti-obesity potential of a CD47-ASO in obese mouse models. Therefore these studies have clinical significance.