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.

项目概要/摘要 三分之一的美国成年人患有肥胖症。肥胖显着影响 许多其他危及生命的疾病的流行，例如 2 型糖尿病， 心血管疾病、癌症等。尽管已经投入了大量资源 为解决这一重大公共卫生威胁而进行的投资，事实是，目前只有有限的资金 已经开发出药物治疗方法来治疗肥胖症。一个在- 迫切需要深入了解肥胖的原因，以便于发现 更有效的治疗方法。人体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。 白色脂肪以脂质形式储存过多的能量，而棕色脂肪则消耗 通过适应性产热（即产生热量）产生过多的能量。一个常见的 人类肥胖的现象是棕色脂肪转化为白色脂肪的过程 认定为美白。逆转棕色脂肪美白激活棕色脂肪功能 发挥抗肥胖作用。本研究的总体目标是调查 脂质运载蛋白 2 (LCN-2)，一种促进棕色脂肪美白的潜在因子。申请人 最近对他的脂肪细胞线粒体功能障碍进行了一系列筛查 模型。 LCN-2 被认为是促使白色变成棕色的主要因素 脂肪组织串扰诱导棕色脂肪美白。因此，提出本提案 评估中心假设：LCN-2，一种来自白色脂肪的分泌因子，是 由线粒体窘迫引起并促进棕色脂肪美白。在目标 1 中，细胞 将利用培养系统（体外）来证明棕色细胞中需要 LCN-2 脂肪美白。在目标 2 中，将提供来自小鼠（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（即冷 不耐受和肥胖）。这项研究将通过定义一部小说来填补知识空白 美白因子有助于了解棕色脂肪组织如何变白。 此外，这项研究具有转化价值，因为 LCN-2 的中和作用 本身或抑制 LCN-2 受体具有巨大的改善潜力 棕色 AT 美白，进而确定减轻肥胖的创新疗法。