CD47 as a therapeutic target for obesity

CD47作为肥胖症的治疗靶点

• 批准号: 10292945
• 负责人: Shuxia Wang
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292945
• 关键词: Adipocytes; Adipose tissue; Animal Model; Animals; Antisense Oligonucleotides; Attenuated; Body Weight; Body fat; Body mass index; Brown Fat; CD47 gene; Carnitine Palmitoyltransferase I; Cell Line; Cell membrane; Cell physiology; Cells; Complex; Cyclic AMP; Cyclic GMP; Data; Development; Diet; Eating; Energy Intake; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Functional disorder; Genes; Genotype; High Fat Diet; Homeostasis; Human Genome; In Vitro; Insulin Resistance; Investigation; Knockout Mice; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Mus; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity Epidemic; Resistance; Respiration; Risk Factors; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; System; Testing; Therapeutic; Thermogenesis; Tissues; Wild Type Mouse; Work; base; blood glucose regulation; clinically significant; combat; comorbidity; diet-induced obesity; fatty liver disease; genome-wide analysis; human subject; immune function; improved; in vivo; knock-down; lipid biosynthesis; lipid metabolism; mouse model; novel; novel therapeutic intervention; obesity development; obesity genetics; obesity treatment; oxidation; prevent; receptor; therapeutic target; tool

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.

棕色脂肪组织 (BAT) 通过 UCP1 介导的非耦合呼吸及其激活来耗散能量 可能代表一种对抗肥胖的治疗策略。初步研究确定了 CD47 的新作用 调节 BAT 功能及其对能量稳态和肥胖发展的贡献。 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 缺陷可以保护小鼠免受饮食影响 通过激活 BAT 功能（例如增强线粒体解偶联和热量）诱导肥胖 (DIO) 生产）和增加能源消耗。这些数据表明 CD47 是 BAT 的负调节因子 活动。因此，抑制CD47信号传导可能是一种新的抗肥胖策略，这进一步有待进一步研究。 最近一项人类全基因组研究显示单核苷酸多态性的关联性 CD47 基因与体重和 BMI 相关。在该提案中，CD47 下调的机制 棕色脂肪细胞功能将在目标 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 信号传导 反义寡核苷酸 (ASO) 治疗可激活 BAT 并预防/改善动物肥胖的发生 模型将在目标 3 中确定。这些研究不仅会提供有关机制的新信息 CD47 下调棕色脂肪功能及其对能量稳态的贡献 肥胖的发展，还测试了 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。