BCFA Metabolism and the Regulation of Energy Balance

BCFA代谢与能量平衡的调节

基本信息

批准号：
10657086
负责人：
Irfan J Lodhi
金额：
$ 51.43万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-25 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657086
关键词：
ATP Synthesis Pathway Adipocytes Adipose tissue Animals Biochemical Branched-Chain Amino Acids Brown Fat CRISPR/Cas technology Cardiovascular Diseases Catabolism Cell Culture Techniques Coenzyme A Consumption Dietary Intervention Energy Metabolism Enzymes Fatty Acids Fatty acid glycerol esters Fatty-acid synthase Futile Cycling Gene Expression Genes Glucose Impairment Insulin Resistance Knock-out Knockout Mice Label LoxP-flanked allele Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Metabolism Mitochondria Mitochondrial Membrane Protein Mus Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Obesity Organelles Oxygen Consumption Pathway interactions Physiological Process Production Proteins Public Health Regulation Respiration Risk Role Site Stimulus Temperature Testing Thermogenesis Up-Regulation Valine Work branched chain fatty acid design diet-induced obesity energy balance fatty acid metabolism fatty acid oxidation gain of function in vivo innovation lipid biosynthesis lipid metabolism loss of function mouse model novel novel therapeutic intervention overexpression oxidation peroxisome response sensor synthetic protein uncoupling protein 1

项目摘要

PROJECT SUMMARY Targeting brown adipose tissue (BAT) function to increase energy expenditure represents an attractive strategy to treat obesity and the associated type 2 diabetes. BAT and the related beige fat express uncoupling protein 1 (UCP1), a mitochondrial membrane protein that uncouples respiration from ATP synthesis and promotes thermogenesis. Paradoxically, UCP1 null mice are only obese when maintained at thermoneutrality, suggesting the existence of alternative mechanisms of thermogenesis. Consistent with this notion, several UCP1- independent ATP-consuming futile cycles have been identified in brown and beige adipocytes. However, the relative contribution of these pathways to the regulation of whole-body energy metabolism remains unclear. Our preliminary studies suggest that peroxisomes, organelles specialized for lipid metabolism, are involved in an alternative mechanism of adipose tissue thermogenesis based on peroxisomal metabolism of branched chain fatty acids (BCFA). Peroxisomes account for up to 20% of total cellular oxygen consumption. Peroxisomal respiration, unlike mitochondrial oxygen consumption, is not linked to ATP synthesis and instead generates heat. Monomethyl (mm) BCFA are synthesized via de novo lipogenesis using a precursor derived from catabolism of branched chain amino acids (BCAA). Our results reveal that cold treatment increases the gene expression of factors involved in mmBCFA synthesis and beta-oxidation in thermogenic fat. A thermogenic stimulus promotes translocation of BCFA synthetic proteins to peroxisomes, the site of BCFA beta-oxidation. Upregulation of BCFA beta oxidation raises the intracellular temperature in brown adipocytes and increases oxygen consumption rate in WT and UCP1 KO brown adipocytes. Together, these results lead us to hypothesize that peroxisomes are involved in a UCP1-independent mechanism of thermogenesis characterized by a futile process of BCFA synthesis and beta-oxidation. Since de novo synthesis of fatty acids is a highly energy-demanding process and peroxisomal beta-oxidation is not linked to ATP production, we further hypothesize that this futile cycle promotes negative energy balance, leading to protection against obesity and insulin resistance. To test this hypothesis, we propose two specific aims. The first aim will use biochemical, cell culture-based, and in vivo approaches to implicate peroxisomes in a futile process of BCFA metabolism. The second aim will use loss-of-function and gain-of-function mouse models of BCFA beta-oxidation to study its role in thermogenesis and whole-body energy metabolism.

项目概要针对棕色脂肪组织 (BAT) 功能来增加能量消耗是一种有吸引力的策略治疗肥胖和相关的 2 型糖尿病。 BAT 和相关的米色脂肪表达解偶联蛋白 1 (UCP1)，一种线粒体膜蛋白，可将呼吸与 ATP 合成解偶联并促进生热作用。矛盾的是，UCP1缺失小鼠只有在保持热中性时才会肥胖，这表明生热作用的替代机制的存在。与这个概念一致，一些 UCP1- 在棕色和米色脂肪细胞中已经发现了独立的 ATP 消耗无效循环。然而，这些途径对全身能量代谢调节的相对贡献仍不清楚。我们的初步研究表明，过氧化物酶体（专门负责脂质代谢的细胞器）参与基于支链过氧化物酶体代谢的脂肪组织产热的替代机制脂肪酸（BCFA）。过氧化物酶体占细胞总耗氧量的 20%。过氧化物酶体与线粒体耗氧不同，呼吸与 ATP 合成无关，而是产生热量。单甲基 (mm) BCFA 使用源自分解代谢的前体通过从头脂肪生成合成支链氨基酸（BCAA）。我们的结果表明冷处理增加了基因表达参与产热脂肪中 mmBCFA 合成和 β-氧化的因素。生热刺激促进 BCFA 合成蛋白易位至过氧化物酶体，即 BCFA β-氧化位点。 BCFA 的上调 β氧化提高棕色脂肪细胞的细胞内温度并增加耗氧率在 WT 和 UCP1 KO 棕色脂肪细胞中。总之，这些结果使我们推测过氧化物酶体是参与以 BCFA 无效过程为特征的独立于 UCP1 的生热机制合成和β-氧化。由于脂肪酸的从头合成是一个高能量需求的过程，过氧化物酶体β-氧化与 ATP 产生无关，我们进一步假设这种无效循环促进负能量平衡，导致预防肥胖和胰岛素抵抗。为了检验这个假设，我们提出两个具体目标。第一个目标将使用生物化学、基于细胞培养的体内方法表明过氧化物酶体参与了 BCFA 代谢的无效过程。第二个目标将使用功能丧失和 BCFA β-氧化功能获得性小鼠模型，用于研究其在产热和全身能量中的作用代谢。