REGULATION OF ADIPOSE TISSUE REMODELING AND ENERGY HOMEOSTASIS

脂肪组织重塑和能量稳态的调节

• 批准号: 10318102
• 负责人: Irfan J Lodhi
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318102
• 关键词: Adipocytes; Adipose tissue; Agonist; Autophagocytosis; Brown Fat; CRISPR/Cas technology; Carrier Proteins; Cell Nucleus; Chloroquine; Complex; Cultured Cells; Development; Diabetes Mellitus; Energy Metabolism; Ethers; Family; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Homeostasis; Importins; Karyopherins; Knockout Mice; Lipids; LoxP-flanked allele; Mediating; Mediator of activation protein; Membrane Proteins; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Nuclear; Nuclear Receptors; Obesity; Oxidoreductase; PPAR alpha; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Proteins; Public Health; Regulation; Role; Testing; Thermogenesis; Thiazolidinediones; Work; base; cofactor; design; improved; inhibition of autophagy; insight; insulin sensitivity; knock-down; lipid biosynthesis; mutant; novel strategies; overexpression; preservation; programs; recruit; synthetic enzyme

Targeting adipose tissue function to decrease adiposity and improve insulin sensitivity could treat obesity and diabetes. The nuclear receptor PPARgamma is a critical regulator of adipose tissue development and function and is activated by the glitazone family of diabetes drugs. The ability of PPARgamma to regulate the development of two functionally distinct types of adipose tissue, brown and white fats, as well as browning of white adipose tissue (WAT), suggests that it may be activated by different partial agonists that in turn promote recruitment of distinct transcriptional cofactors. Our previous efforts to understand the contribution of adipose tissue lipogenesis to the endogenous activation of PPARgamma led to the identification of PexRAP (Peroxisomal Reductase Activating PPARgamma), a peroxisomal membrane protein that synthesizes ether lipids, potential partial agonists for PPARgamma. In this project, we will study the role of PexRAP in adipose tissue remodeling. Although PexRAP is abundantly present in WAT and its expression increases during white adipogenesis, the protein levels of PexRAP in mature brown adipose tissue (BAT) are low. The PexRAP protein, but not its mRNA, dramatically decreases during brown adipogenesis. Inhibition of autophagy stabilized PexRAP protein levels, suggesting that PexRAP is targeted for degradation during BAT development. PexRAP inactivation in mice promotes adipocyte browning, increased energy expenditure and decreased adiposity, while its overexpression in cultured cells inhibits thermogenic gene expression. Identification of PexRAP-interacting proteins suggests that the function of PexRAP in adipocytes extends well beyond its role as a peroxisomal lipid synthetic enzyme. PexRAP is also present in the nucleus, where it interacts with regulators of adipocyte gene expression, including a component of the Mediator complex. Based on these results, we hypothesize that nuclear localized PexRAP functions as a molecular switch that programs adipose tissue remodeling by repressing thermogenesis in beige adipocytes and promoting lipid storage in white adipocytes. To test this hypothesis, we propose three specific aims. In aim 1, we will study the physiological importance of PexRAP degradation in the regulation of thermogenesis and energy homeostasis. In aim 2, we will evaluate the transcriptional regulatory role of PexRAP in adipocytes. The third aim will identify the role of a PexRAP-associated Mediator component in adipocyte gene expression, adipose tissue development and metabolic homeostasis. Together, this work will provide a significant insight into molecular mechanisms involved in adipose tissue remodeling. Understanding how PexRAP and its associated proteins control adipocyte identity will be critical for designing strategies to increase brown and beige fat mass to treat obesity.

针对脂肪组织功能来减少肥胖并提高胰岛素敏感性可以治疗肥胖和糖尿病。核受体 PPARgamma 是脂肪组织发育和功能的关键调节因子，由糖尿病药物格列酮家族激活。 PPARgamma 能够调节两种功能不同类型的脂肪组织（棕色脂肪和白色脂肪）的发育，以及白色脂肪组织 (WAT) 的褐变，这表明它可能被不同的部分激动剂激活，从而促进脂肪组织的募集。不同的转录辅助因子。我们之前努力了解脂肪组织脂肪生成对 PPARgamma 内源性激活的贡献，从而鉴定出 PexRAP（过氧化物酶体还原酶激活 PPARgamma），这是一种合成醚脂质的过氧化物酶体膜蛋白，是 PPARgamma 的潜在部分激动剂。在这个项目中，我们将研究 PexRAP 在脂肪组织重塑中的作用。尽管 PexRAP 大量存在于 WAT 中，并且其表达在白色脂肪形成过程中增加，但成熟棕色脂肪组织 (BAT) 中 PexRAP 的蛋白水平较低。 PexRAP 蛋白（而非其 mRNA）在棕色脂肪生成过程中显着减少。自噬的抑制稳定了 PexRAP 蛋白水平，表明 PexRAP 是 BAT 发育过程中降解的目标。 PexRAP 在小鼠体内失活会促进脂肪细胞褐变、增加能量消耗并减少肥胖，而其在培养细胞中的过度表达会抑制生热基因表达。 PexRAP 相互作用蛋白的鉴定表明 PexRAP 在脂肪细胞中的功能远远超出了其作为过氧化物酶体脂质合成酶的作用。 PexRAP 也存在于细胞核中，与脂肪细胞基因表达的调节因子（包括介导复合物的一个组成部分）相互作用。基于这些结果，我们假设核定位的 PexRAP 作为分子开关发挥作用，通过抑制米色脂肪细胞中的生热作用并促进白色脂肪细胞中的脂质储存来编程脂肪组织重塑。为了检验这一假设，我们提出了三个具体目标。在目标 1 中，我们将研究 PexRAP 降解在生热和能量稳态调节中的生理重要性。在目标 2 中，我们将评估 PexRAP 在脂肪细胞中的转录调节作用。第三个目标是确定 PexRAP 相关介导成分在脂肪细胞基因表达、脂肪组织发育和代谢稳态中的作用。总之，这项工作将为脂肪组织重塑的分子机制提供重要的见解。了解 PexRAP 及其相关蛋白如何控制脂肪细胞特性对于设计增加棕色和米色脂肪量以治疗肥胖的策略至关重要。

项目成果

Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis.

• DOI: 10.1126/sciadv.ade7864
• 发表时间: 2023-02-24
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Johnson JM;Peterlin AD;Balderas E;Sustarsic EG;Maschek JA;Lang MJ;Jara-Ramos A;Panic V;Morgan JT;Villanueva CJ;Sanchez A;Rutter J;Lodhi IJ;Cox JE;Fisher-Wellman KH;Chaudhuri D;Gerhart-Hines Z;Funai K
• 通讯作者: Funai K

Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis.

脂肪组织过氧化物酶体脂质合成通过 LXR 依赖性脂肪生成协调肥胖和胰岛素抵抗。

• DOI: 10.1016/j.molmet.2024.101913
• 发表时间: 2024
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Kleiboeker,Brian;He,Anyuan;Tan,Min;Lu,Dongliang;Hu,Donghua;Liu,Xuejing;Goodarzi,Parniyan;Hsu,Fong-Fu;Razani,Babak;Semenkovich,ClayF;Lodhi,IrfanJ
• 通讯作者: Lodhi,IrfanJ