Role of UCP1 in the inter-organ lipid cycle engaged by dietary methionine restric

UCP1 在饮食蛋氨酸限制参与的器官间脂质循环中的作用

• 批准号: 8735622
• 负责人: Desiree Wanders
• 金额: $ 1.16万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735622
• 关键词: Address; Adipose tissue; Affect; Biochemical; Chronic; Collaborations; Comorbidity; Consumption; Coupled; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Euglycemic Clamping; Evaluation; Event; Fasting; Fatty acid glycerol esters; Genes; Glucose; Glucose Clamp; Goals; Healthcare; Hepatic Tissue; Housing; Insulin Resistance; Knockout Mice; Lead; Letters; Link; Lipids; Liver; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methionine; Molecular; Molecular Target; Mus; Obesity; Organ; Pathway interactions; Peripheral; Phenotype; Physiological; Play; Population; Publishing; Quality of life; Regulation; Relative (related person); Research; Role; Series; Substrate Cycling; Sympathetic Nervous System; Temperature; Testing; Tissues; Translating; Work; dietary restriction; economic impact; effective therapy; energy balance; fatty acid oxidation; feeding; in vivo; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; loss of function; nutrition; public health relevance; response

DESCRIPTION (provided by applicant): Obesity and diabetes affect quality of life of a large portion of the national population and has a significant economic impact on healthcare. Understanding the precise molecular events that lead to insulin resistance and metabolic syndrome will translate into more effective treatments. We have shown that dietary methionine restriction (MR) produces a coordinated series of physiological responses that include increased energy expenditure (EE), reduced fat deposition, and a profound enhancement of insulin sensitivity. The metabolic effects of dietary MR are accompanied by transcriptional responses in liver and adipose tissue that reduce circulating and tissue lipids. Our published and preliminary data provide compelling evidence that dietary MR increases UCP1 expression in both brown and white adipose tissue through increases in sympathetic nervous system (SNS) activity, but it has not been established whether increased UCP1 expression or function is an essential mediator of one or more of the physiological responses to dietary MR. Thus, a key objective of our proposal is to determine the significance of modulation of UCP1 by dietary MR in producing the resulting metabolic phenotype. A rigorous evaluation of substrate switching in peripheral tissues during the transition from fasting to the fed state, coupled with in vivo measures of de novo lipogenesis, indicates that dietary MR enhances energetically inefficient conversion of glucose to lipid in the fed state when rates of EE are highest. Cold exposure produces a similar induction of inefficient glucose-dependent lipogenesis in adipose tissue to support the simultaneous increase in fatty acid oxidation that occurs during cold exposure. This response also occurs in cold-exposed mice lacking UCP1, suggesting that increased SNS-dependent, but UCP1-independent substrate cycling is an important component of the thermo genic response. We provide compelling new data showing that UCP1 plays an essential, previously unappreciated role in regulating lipid cycling between liver and adipose tissue in a manner that impacts in vivo insulin sensitivity. Thus, our overall hypothesis is that UCP1 plays an essential role in the integration of lipid metabolism between liver and adipose tissue, and the remodeling of peripheral lipid metabolism and increase in insulin sensitivity produced by dietary MR utilizes SNS-dependent regulation of UCP1 to affect both metabolic responses. Accordingly, our Specific Aims will test the hypotheses that 1) the ability of dietary MR to remodel the integration of lipid metabolism between liver and adipose tissue is regulated by and dependent upon UCP1, and 2) UCP1 is essential and necessary for dietary MR to enhance insulin sensitivity. In Aim 1, we will use UCP1-/- mice to determine whether UCP1 is necessary for dietary MR to increase EE and reciprocally remodel lipid metabolism in adipose tissue and liver. In Aim 2, we will employ a similar loss of function approach to determine the role of UCP1 in the enhancement of overall and tissue-specific insulin sensitivity by dietary MR. The results of the proposed studies will provide important new mechanistic insights into how dietary MR affects lipid metabolism and energy balance.

描述（由申请人提供）：肥胖和糖尿病会影响大部分国家人口的生活质量，并对医疗保健产生重大的经济影响。了解导致胰岛素抵抗和代谢综合征的精确分子事件将转化为更有效的治疗方法。我们已经表明，饮食中的蛋氨酸限制（MR）产生一系列协调的生理反应，包括增加能量消耗（EE），脂肪沉积减少以及胰岛素敏感性的深刻增强。饮食MR的代谢作用伴随着肝脏和脂肪组织中的转录反应，以减少循环和组织脂质。我们发表的和初步的数据提供了令人信服的证据，表明饮食中的MR通过增加交感神经系统（SNS）活性增加了棕色和白色脂肪组织中的UCP1表达，但是尚未确定UCP1表达或功能增加是对饮食MR的生理反应的必不可少的介体。因此，我们建议的一个关键目的是确定饮食中MR在产生所得代谢表型中对UCP1调节的重要性。从禁食到美联储状态的过渡期间，对外周组织中的底物切换的严格评估，再加上从头脂肪生成的体内测量，表明当EE速率最高时，饮食中的MR会增强饮食在FED状态的能量效率无效的葡萄糖转化为脂质。冷暴露在脂肪组织中产生类似诱导的葡萄糖依赖性脂肪形成，以支持冷暴露期间发生的脂肪酸氧化的同时增加。这种反应也发生在缺乏UCP1的冷暴露小鼠中，这表明SNS依赖性增加，但是UCP1独立的底物循环是Thermo Genic响应的重要组成部分。我们提供了令人信服的新数据，表明UCP1在调节肝脏和脂肪组织之间的脂质循环中起着必不可少的，以前没有批准的作用，以影响体内胰岛素敏感性的方式。因此，我们的总体假设是，UCP1在肝脏和脂肪组织之间脂质代谢的整合以及外周脂质代谢的重塑以及饮食中胰岛素敏感性的提高中起着至关重要的作用，饮食中的MR MR依赖于UCP1对UCP1的调节对UCP1的调节对两种代谢反应都有影响。因此，我们的具体目标将检验以下假设，即1）饮食MR重塑整合的能力 肝脏和脂肪组织之间的脂质代谢的调节和依赖于UCP1，而2）UCP1对于增强胰岛素敏感性是必不可少的，并且是必不可少的。在AIM 1中，我们将使用UCP1 - / - 小鼠来确定UCP1是否需要饮食中的MR增加EE和相互重塑脂肪组织和肝脏中的EE和相互重塑的脂质代谢。在AIM 2中，我们将采用类似的功能方法来确定UCP1在通过饮食MR提高整体和组织特异性胰岛素敏感性中的作用。拟议研究的结果将为饮食MR如何影响脂质代谢和能量平衡提供重要的新机械见解。