Perilipin 5 in the Regulation of Adipose Tissue Function

Perilipin 5 在脂肪组织功能调节中的作用

• 批准号: 10735422
• 负责人: PERRY E BICKEL
• 金额: $ 54.12万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735422
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agonists; Adult; Affect; Agonist; Alleles; Attention; Biogenesis; Blood Glucose; Body Weight Changes; Body Weight decreased; Brown Fat; Cardiometabolic Disease; Cardiovascular Diseases; Catecholamines; Cell Nucleus; Cell Size; Crista ampullaris; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Distal; Dose; Doxycycline; Economic Burden; Energy Metabolism; Event; Family; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Foundations; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Health; High Fat Diet; Histology; Human; Hypertrophy; Image; Insulin; Intervention; Knock-out; Knowledge; Lipids; Lipolysis; Literature; Liver; LoxP-flanked allele; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Mitochondria; Modeling; Mouse Strains; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obese Mice; Obesity; Outer Mitochondrial Membrane; Pharmaceutical Preparations; Phosphorylation; Physiological; Prevalence; Prevention; Proteins; Publishing; Pyruvate; Regulation; Research; Respiration; Risk Factors; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Structure; Surface; Testing; Therapeutic; Thermogenesis; Tissues; Weight; Weight maintenance regimen; Work; cancer risk; cardiometabolic risk; cardiometabolism; cold stress; diet-induced obesity; energy balance; experimental study; fat burning; feeding; gain of function; glucose metabolism; glucose tolerance; healthspan; improved; in vivo; inflammatory marker; insight; insulin sensitivity; lipid metabolism; loss of function; member; mouse model; mutant; non-alcoholic fatty liver disease; novel strategies; novel therapeutic intervention; novel therapeutics; obesity treatment; oxidation; perilipin; pharmacologic; prevent; programs; rational design; response; synergism; uptake

Project Abstract/Summary The rising prevalence of obesity and type 2 diabetes threatens to limit human healthspan by increasing the risks for cancer and cardiometabolic disease and to impose overwhelming economic burdens. New therapeutic strategies are urgently needed. Since the discovery of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled mitochondrial respiration. Advanced imaging in humans has revealed a favorable correlation between brown fat mass and cardiometabolic risk factors. A major gap in the field is a safe and effective pharmacological strategy to activate brown and/or beige adipocytes to promote negative energy balance, reverse obesity, and mitigate obesity-related metabolic disorders, such type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The overall goal of this application is to provide proof-of-concept for one such strategy that has been suggested by the lab’s long- standing research program on Perilipin 5 (PLIN5), a member of the Perilipin family of lipid droplet proteins that is expressed in oxidative tissues, including brown adipose tissue (BAT). A growing body of literature from our lab and others has implicated PLIN5 not only in the regulation of lipolysis at the lipid droplet surface, but also in the regulation of gene expression via interactions in the nucleus with SIRT1 and PGC1a and in the tethering of lipid droplets to mitochondria. Our published work in mice has shown that PLIN5 is required for the metabolic, transcriptional, and mitochondrial adaptations of BAT to cold stress. We have also shown that PLIN5 gain-of-function in BAT of mice can prevent glucose intolerance and fatty liver from high-fat diet and promote healthy remodeling of white adipose tissue (WAT) with prevention of adipocyte hypertrophy. In this renewal application we propose to test the hypothesis that promoting PLIN5 expression in BAT in conjunction with b3 adrenergic receptor agonist treatment of diet-induced obese mice will reverse adipocyte hypertrophy in WAT, reverse obesity, and reverse glucose intolerance. Aim 1 will elucidate the metabolic and signaling pathways responsible for the effects of PLIN5 on mitochondrial form and function in BAT and on systemic lipid and glucose metabolism by means of genetic mouse models, in vivo structure- function studies, and mechanistic mitochondrial experiments. Aim 2 will interrogate the signaling pathways and physiological responses associated with treatment of diet-induced obesity with a 2-hit intervention built on augmentation of PLIN5 in BAT in synergistic combination with b3 adrenergic receptor agonist treatment. Successful completion of these Aims may establish the conceptual foundation for a new therapeutic paradigm for treatment of obesity that is efficacious but at lower, non-toxic doses of existing medications.

项目摘要/总结 肥胖和 2 型糖尿病患病率的上升可能会限制人类的健康寿命 癌症和心脏代谢疾病的风险，并造成巨大的经济负担。新的 迫切需要治疗策略。自从发现功能性棕色和米色脂肪细胞以来 成年人，很多注意力都集中在利用这些产热脂肪细胞的能力 通过解耦的线粒体呼吸以热量的形式耗散多余的能量。人类先进成像 揭示了棕色脂肪量与心脏代谢危险因素之间存在良好的相关性。一个重大差距 该领域有一种安全有效的药理学策略来激活棕色和/或米色脂肪细胞 促进负能量平衡，逆转肥胖，减轻与肥胖相关的代谢紊乱，例如 2 型糖尿病、心血管疾病和非酒精性脂肪肝疾病。本次活动的总体目标 该应用程序的目的是为实验室长期建议的一种策略提供概念验证。 Perilipin 5 (PLIN5) 的常设研究计划，Perilipin 脂滴蛋白家族的成员 在氧化组织中表达，包括棕色脂肪组织 (BAT)。不断增长的文学作品 我们实验室和其他人的研究表明 PLIN5 不仅参与脂滴脂肪分解的调节 表面，而且还通过细胞核中与 SIRT1 和 PGC1a 的相互作用来调节基因表达 以及脂滴与线粒体的束缚。我们发表的小鼠研究表明 PLIN5 BAT 的代谢、转录和线粒体适应冷应激所需的。我们有 还表明，小鼠 BAT 中的 PLIN5 功能获得可以预防葡萄糖不耐症和脂肪肝 高脂肪饮食并促进白色脂肪组织（WAT）的健康重塑，预防脂肪细胞 肥大。在此更新应用中，我们建议测试促进 PLIN5 表达的假设 BAT 联合 b3 肾上腺素能受体激动剂治疗饮食诱导的肥胖小鼠将逆转 WAT 中脂肪细胞肥大，逆转肥胖，逆转葡萄糖耐受不良。目标 1 将阐明 代谢和信号通路负责 PLIN5 对线粒体形式和功能的影响 BAT 以及通过遗传小鼠模型、体内结构对全身脂质和葡萄糖代谢的影响 功能研究和线粒体机械实验。目标 2 将询问信号通路 以及与通过建立 2-hit 干预措施治疗饮食引起的肥胖相关的生理反应 与 b3 肾上腺素能受体激动剂治疗协同组合增强 BAT 中的 PLIN5。 成功完成这些目标可能会为新的治疗方法奠定概念基础 治疗肥胖症的范例是有效的，但现有药物的剂量较低，无毒。

项目成果

Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance.

• DOI: 10.1038/s41467-021-23601-2
• 发表时间: 2021-06-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gallardo-Montejano VI;Yang C;Hahner L;McAfee JL;Johnson JA;Holland WL;Fernandez-Valdivia R;Bickel PE
• 通讯作者: Bickel PE

Qa-SNARE syntaxin 18 mediates lipid droplet fusion with SNAP23 and SEC22B.

• DOI: 10.1038/s41421-023-00613-4
• 发表时间: 2023-11-21
• 期刊: CELL DISCOVERY
• 影响因子: 33.5
• 作者: Fu, Yuhui;Ding, Binbin;Liu, Xiaoxia;Zhao, Shangang;Chen, Fang;Li, Linsen;Zhu, Yi;Zhao, Jingxuan;Yuan, Zhen;Shen, Yafeng;Yang, Chaofeng;Shao, Mengle;Chen, She;Bickel, Perry E.;Zhong, Qing
• 通讯作者: Zhong, Qing