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.

项目摘要靶向棕色脂肪组织（BAT）功能以增加能量消耗代表了一个有吸引力的策略治疗肥胖症和相关的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，它使呼吸与ATP合成并促进热发生。自相矛盾的是，UCP1 null小鼠仅在保持热统治时才肥胖，这表明生热的替代机制的存在。与这个概念一致，几个UCP1- 在棕色和米色脂肪细胞中已经确定了独立的ATP徒劳循环。但是，这些途径对调节全身能量代谢的相对贡献尚不清楚。我们的初步研究表明，过氧化物酶体（专门用于脂质代谢的细胞器）参与基于分支链的过氧化物酶体代谢的脂肪组织热发生的替代机制脂肪酸（BCFA）。过氧化物酶体占总细胞氧消耗的20％。过氧化物酶体与线粒体氧的消耗不同，呼吸与ATP合成无关，而是产生热量。单甲基（MM）BCFA通过从头脂肪生成合成，使用源自分解代谢的前体分支链氨基酸（BCAA）。我们的结果表明，冷处理增加了热脂肪脂肪中MMBCFA合成和β-氧化的因素。热刺激促进 BCFA合成蛋白转移到过氧化物酶体（BCFAβ-氧化位点）。 BCFA上调 β氧化升高棕色脂肪细胞的细胞内温度，并提高氧气消耗率在WT和UCP1 KO Brown脂肪细胞中。总之，这些结果使我们假设过氧化物酶体是涉及以UCP1无关的生热机制为特征，其特征是BCFA的徒劳过程合成和β-氧化。由于从头合成脂肪酸是一个高能量的过程，并且过氧化物酶体β-氧化与ATP的产生无关，我们进一步假设这种徒劳的周期会促进负能量平衡，从而防止肥胖和胰岛素抵抗。为了检验这一假设，我们提出了两个具体目标。第一个目的将使用生化，基于细胞培养和体内的方法在BCFA代谢的徒劳过程中暗示过氧化物酶体。第二个目标将使用功能丧失和 BCFAβ-氧化的功能性小鼠模型研究其在热生成和全身能量中的作用代谢。