Lipocalin-2, a mitokine that mediates white to brown fat crosstalk

Lipocalin-2，一种介导白色至棕色脂肪串扰的丝分裂素

• 批准号: 10645353
• 负责人: Yu An
• 金额: $ 11.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645353
• 关键词: Adipocytes; Adipose tissue; Adult; American; Amyloid beta-Protein Precursor; Automobile Driving; Biochemical; Brown Fat; Cardiovascular Diseases; Cell Culture System; Cells; Consumption; Data; Disease; Distress; Energy Intake; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Functional disorder; Genes; Goals; Grant; High Fat Diet; Histologic; Homeostasis; Human; Impairment; In Vitro; Investments; Kinetics; Knock-out; Knockout Mice; Knowledge; LCN2 gene; Life; Lipids; Liver; Malignant Neoplasms; Measures; Mediating; Mediator; Mentored Research Scientist Development Award; Metabolic; Metabolic Diseases; Methods; Mitochondria; Modeling; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Prevalence; Process; Property; Proteins; Public Health; Recombinant Proteins; Recombinants; Resources; Role; Series; Skeletal Muscle; Testing; Therapeutic; Thermogenesis; Tissues; Wild Type Mouse; comorbidity; diet-induced obesity; energy balance; improved; in silico; in vivo; innovation; knock-down; mitochondrial dysfunction; novel; novel therapeutics; obesity development; overexpression; pharmacologic; receptor; screening; therapeutically effective

Project Summary/Abstract One third of American adults are suffering from obesity. Obesity significantly contributes to the prevalence of numerous other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been invested to resolve this major public health threat, the fact is that, currently, only limited methods of pharmacological therapeutics have been developed to treat obesity. An in- depth understanding of the reasons for obesity is urgently needed to facilitate finding more effective therapeutics. There are two types of fat tissue in humans: white and brown adipose tissue. They have different morphologies and perform distinct functions. While white fat stores excessive energy in the form of lipids, brown fat consumes excessive energy through adaptive thermogenesis (i.e., generating heat). A common phenomenon in human obesity is the conversion of brown fat into white fat, a process identified as whitening. Reversing brown fat whitening activates brown fat function and exerts anti-obesity effects. The overarching goal of this study is to investigate the role of lipocalin 2 (LCN-2), a potential factor that promotes brown fat whitening. The applicant recently performed a series of screenings in his adipocyte mitochondrial dysfunction model. LCN-2 was suggested to be a leading factor that drives the white to brown adipose tissue crosstalk to induce brown fat whitening. Therefore, this proposal is set out to evaluate the central hypotheses: LCN-2, a secreting factor from the white fat, is induced by mitochondrial distress and promotes brown fat whitening. In Aim 1, cell culture systems (in vitro) will be utilized to demonstrate that LCN-2 is required in brown fat whitening. In Aim 2, evidence from mice (in vivo) will be provided to further evaluate the role of LCN-2 in brown fat whitening and metabolic consequences (i.e., cold intolerance and obesity). This study will fill a knowledge gap through defining a novel whitening factor in understanding how the brown adipose tissue becomes whitened. Furthermore, this study has translational merits because either neutralization of LCN-2 per se or inhibition of the LCN-2 receptor holds an enormous potential to ameliorate brown AT whitening and, in turn, to identify innovative therapeutics that alleviate obesity.

项目摘要/摘要 美国成年人中有三分之一患有肥胖症。肥胖有显着贡献 为了患许多其他威胁生命的疾病（例如2型糖尿病）的患病率， 心血管疾病，癌症等 投资用于解决这一重大公共卫生威胁，事实是，目前只有限制 已经开发了药理学治疗方法来治疗肥胖症。一个 迫切需要对肥胖原因的深度理解以促进发现 更有效的治疗学。人类有两种类型的脂肪组织：白色和 棕色脂肪组织。它们具有不同的形态并执行不同的功能。 白脂肪以脂质的形式储存过多的能量，而棕色脂肪消耗 通过自适应生热（即产生热量）通过过多的能量。常见 人肥胖中的现象是将棕色脂肪转化为白脂的转化 被确定为美白。逆转棕色脂肪美白会激活棕色脂肪功能和 发挥抗肥胖作用。这项研究的总体目标是调查 Lipocalin 2（LCN-2），这是促进棕色脂肪美白的潜在因素。申请人 最近在他的脂肪细胞线粒体功能障碍中进行了一系列检查 模型。建议LCN-2是驱动白色至棕色的主要因素 脂肪组织串扰诱导棕色脂肪美白。因此，该提议已列出 评估中心假设：LCN-2是白脂肪的分泌因子，是 通过线粒体遇险诱导并促进棕色脂肪美白。在AIM 1中 培养系统（体外）将用于证明棕色需要LCN-2 脂肪增白。在AIM 2中，将提供小鼠（体内）的证据以进一步评估 LCN-2在棕色脂肪美白和代谢后果中的作用（即冷 不宽容和肥胖）。这项研究将通过定义小说来填补知识差距 了解棕色脂肪组织如何变白的美白因素。 此外，这项研究具有翻译优点，因为LCN-2的中和 本身或LCN-2受体的抑制作用具有改善的巨大潜力 美白时棕色，反过来又确定了减轻肥胖症的创新治疗剂。