Mechanisms of Obesity in Mice with Neuron-Specific Lipoprotein Lipase Deficiency

神经元特异性脂蛋白脂肪酶缺乏小鼠的肥胖机制

• 批准号: 8668938
• 负责人: Robert H Eckel
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668938
• 关键词: Adverse effects; Age; Aging; Applications Grants; Body Weight; Brain; Brain region; Breast; Brown Fat; Cardiovascular Diseases; Cell Line; Cells; Cessation of life; Colon; Comorbidity; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Dyslipidemias; Eating; Energy Metabolism; Enzymes; Epidemic; Esophageal; Event; Fatty Acids; Gene Expression; Glucose Intolerance; Grant; Health; Hippocampus (Brain); Hydrolysis; Hyperphagia; Hyperplasia; Hypertension; Hypertrophy; Hypothalamic structure; In Vitro; Insulin; Insulin Resistance; Kidney; Kidney Diseases; Life Style; Lipids; Lipoprotein (a); Lipoproteins; Location; Macronutrients Nutrition; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Morbid Obesity; Mus; Nervous system structure; Neurons; Obesity; Obesity associated cancer; Obstructive Sleep Apnea; Ovarian; Overweight; Pancreas; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Physical activity; Physiological; Physiology; Play; Prevention approach; Receptor Gene; Regulation; Request for Applications; Research Design; Risk; Role; Series; Site; Testing; Therapeutic; Tissues; Triglycerides; Up-Regulation; Weight; Work; World Health; clinically relevant; design; energy balance; enzyme activity; glucose metabolism; glucose tolerance; glucose transport; improved; in vivo; insight; interest; lipoprotein lipase; lipoprotein triglyceride; novel strategies; obesity treatment; oxidation; prevent; receptor; research study; uptake

DESCRIPTION (provided by applicant): The long-term objective of this application is to uncover mechanisms of body weight regulation through a newly discovered pathway mediated by the enzyme lipoprotein lipase (LPL) in the neuron. LPL is the rate limiting enzyme for the uptake of fatty acids from the hydrolysis of circulating triglyceride-rich lipoproteins for lipid storage and/or oxidation in peripheral tissues. LPL is also present throughout the nervous system including neurons in the hippocampus, hypothalamus, and other brain regions. Mice with neuron-specific deletion of LPL (NEXLPL-/-) are obese on dietary chow by 6 months, and heterozygous mice (NEXLPL) also become obese between 6 and 12 mo. In both NEXLPL-/- and NEXLPL a period of hyperphagia precedes obesity followed by marked reductions in metabolic rate ensue. In both NEXLPL-/- and NEXLPL mice, substantial increases in AgRP mRNA in the hypothalamus occur before the onset of obesity and are less elevated but persist after obesity develops. Preliminary data suggest that the LPL-dependent deficiency and metabolism of specific PUFAs in the hypothalamus leads to this up-regulation of AgRP gene expression. In Specific Aim #1 well characterized hypothalamic cell lines will be used to test whether LPL deficiency directly leads to increased AgRP gene expression in vitro and whether such regulation depends on the enzyme activity of LPL. Mechanistic studies are designed to pinpoint whether LPL functions in the hypothalamus by regulating fatty acid uptake and whether such regulation also relates to insulin action in these cells. In Specific Aim #2 mice deficient in LPL only in AgRP-producing neurons will be generated to demonstrate that AgRP-producing neurons in NEXLPL-/- mice are the major site of regulation of energy balance and body weight. Studies to evaluate how dietary fatty acids regulate the phenotype are also planned. Finally, despite the presence of severe obesity at 12 mo, NEXLPL-/- mice have better glucose tolerance than littermate controls, and also demonstrate increases in Mc3r gene expression in the hypothalamus, marked brown adipose tissue (BAT) hyperplasia/hypertrophy and increased BAT UCP-1 gene expression. Experiments in this aim will be directed to determining the mechanism of improved glucose metabolism despite obesity in NEXLPL-/- mice. We believe the clinical relevance of this work relates not only to how dietary lipids carried in lipoproteins control energy balance and body weight, but to mechanisms by which BAT is stimulated and glucose tolerance is preserved. Because obesity is epidemic, more insight into the physiology of body weight regulation including how obesity relates to glucose intolerance is needed. Moreover, from this work novel approaches to the prevention and or treatment of obesity by lifestyle and/or new drugs may be possible. Overall, this is the first observation that TG-rich lipoproteins and their metabolism by LPL in the brain has physiologic relevance, and through a series of experiments we hope to reveal mechanisms of how TG-rich lipoprotein sensing and metabolism in the brain impact energy balance and body weight regulation.

描述（由申请人提供）：该应用的长期目标是通过神经元中的酶脂蛋白脂肪酶（LPL）介导的新发现的途径来揭示体重调节的机制。 LPL是从循环甘油三酸酯富脂蛋白的水解中摄取脂肪酸的速率，用于脂质储存和/或外周组织中的氧化。 LPL在整个神经系统中也存在，包括海马，下丘脑和其他大脑区域的神经元。 LPL（nexlpl - / - ）具有神经元特异性缺失的小鼠在饮食中肥胖6个月，而杂合小鼠（Nexlpl）也会在6至12个月之间肥胖。在nexlpl - / - 和nexlpl中，多晶状体的周期先于肥胖症，然后明显降低代谢率。在Nexlpl - / - 和Nexlpl小鼠中，下丘脑中的AgRP mRNA的大幅增加发生在肥胖发作之前，并且升高较少，但肥胖发展后持续存在。初步数据表明，下丘脑中特定PUFA的LPL依赖性缺陷和代谢导致AGRP基因表达的这种上调。在特定的目标＃1中，下丘脑细胞系将用于测试LPL缺乏是否直接导致体外AGRP基因表达增加，并且这种调节是否取决于LPL的酶活性。机械研究旨在确定LPL是否通过调节脂肪酸摄取以及这种调节是否也与这些细胞中的胰岛素作用有关。在仅在产生AGRP的神经元中缺乏LPL的特定目标中，才能证明Nexlpl - / - 小鼠中产生AGRP的神经元是能量平衡和体重调节体重的主要部位。还可以计划评估饮食脂肪酸如何调节表型的研究。最后，尽管在12 mo处存在严重的肥胖症，但Nexlpl - / - 小鼠的葡萄糖耐受性比同窝对照更好，并且还表明下丘脑中MC3R基因表达的升高，明显的棕色脂肪组织（BAT）增生/肥大和BAT UCP-1基因表达增加。尽管Nexlpl - / - 小鼠肥胖，但该目标中的实验将用于确定改善葡萄糖代谢的机制。我们认为，这项工作的临床相关性不仅与脂蛋白中的饮食脂质如何控制能量平衡和体重有关，而且与刺激BAT的机制保持了刺激并保留葡萄糖耐受性的机制。由于肥胖症是流行病的，因此需要更多地了解体重调节的生理学，包括肥胖与葡萄糖不耐症的关系。此外，从这种新颖的方法来看，可以通过生活方式和/或新药对肥胖进行预防和治疗。总体而言，这是第一个观察到，LPL在大脑中富含TG的脂蛋白及其代谢具有生理意义，并且通过一系列实验，我们希望揭示有关富含TG的富含TG的脂蛋白感应和代谢的机制。

项目成果

Lipoprotein lipase in the brain and nervous system.

• DOI: 10.1146/annurev-nutr-071811-150703
• 发表时间: 2012-08-21
• 期刊: Annual review of nutrition
• 影响因子: 8.9
• 作者: Wang H;Eckel RH
• 通讯作者: Eckel RH

What are lipoproteins doing in the brain?

• DOI: 10.1016/j.tem.2013.10.003
• 发表时间: 2014-01
• 期刊: TRENDS IN ENDOCRINOLOGY AND METABOLISM
• 影响因子: 10.9
• 作者: Wang, Hong;Eckel, Robert H.
• 通讯作者: Eckel, Robert H.