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Lipid metabolism and adipose tissue function

Lipid metabolism and adipose tissue function
脂质代谢和脂肪组织功能
批准号:
10390756
负责人:
Jun Liu
金额:
$50.49万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-12-01 至 2025-11-30

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中文摘要
翻译
项目摘要 肥胖症的患病率在世界范围内已上升到流行病的程度。功能障碍性白色脂肪 脂肪组织(WAT)和棕色脂肪组织(BAT)与肥胖症的发病机制有关, 相关代谢综合征。BAT密集地布满线粒体,需要脂肪酸(FA)氧化, 支持产热作用。相比之下,WAT作为主要的能量储存器官, WAT在环境温度下相对较低。慢性冷暴露诱导皮下WAT的布朗宁 变成具有增加的FA氧化能力的产热米色AT。虽然FA氧化是已知的, 关键和基本的代谢终点在人类和啮齿动物,它是不完全清楚如何 脂肪细胞脂肪酸氧化是调节后,以及它如何有助于全身能量 以自主的方式进行新陈代谢。在这方面,我们的初步研究提供了令人信服的证据, 由载脂蛋白6(ApoL 6)编码的蛋白是线粒体三功能蛋白的选择性调节剂 (TFP)是催化FA β-氧化的关键酶。ApoL 6在WAT中高表达并分化为 脂肪细胞相反,BAT通常表达低水平的ApoL 6,其在肥胖或肥胖期间增加。 热中性致白。我们发现,在基础条件下,ApoL 6定位于线粒体, 导致线粒体FA氧化减弱。在BAT中表达ApoL 6的转基因小鼠表现出 冷暴露时产热能力较低,能量消耗沿着降低, 肥胖症相反,接受HFD的脂肪ApoL 6敲除小鼠显示体重和脂肪量降低, 增益基于这些初步的数据,我们假设通过抑制线粒体FA氧化, 从而降低能量消耗,ApoL 6在以下方面起关键作用:(1)维持WAT中的脂肪储存, 全身能量平衡,以及(2)阻碍变白BAT的非颤抖产热。有三 目的:在目的1中,我们将确定在脂肪细胞FA中,脑内定位的ApoL 6的机制作用。 氧化通过使用增益和损失的功能细胞模型。在目标2中,我们将确定脂肪特异性 小鼠ApoL 6消融影响饮食诱导的肥胖及其相关代谢变化,包括胰岛素 阻力在目标3中,我们将使用功能丧失和获得小鼠模型来定义ApoL 6在以下中的作用: 在肥胖和热中性诱导的美白过程中BAT产热的调节。产生的证据 从这个项目应该提供新的见解的分子基础上调节FA氧化, 脂肪组织中的能量代谢,从而推进开发新的 治疗肥胖和2型糖尿病的方法。
英文摘要
Project Summary The prevalence of obesity has increased worldwide to epidemic proportions. Dysfunctional white adipose tissue (WAT) and brown adipose tissue (BAT) have been implicated in the pathogenesis of obesity and its related metabolic syndrome. BAT is densely packed with mitochondria and requires fatty acid (FA) oxidation to support thermogenesis. In comparison, WAT serves as a main energy storage organ and the FA oxidation in WAT is relatively low at ambient temperature. Chronic cold exposure induces browning of subcutaneous WAT to become thermogenic beige AT with increased FA oxidation capacity. Although FA oxidation is known to be a critical and fundamental metabolic end point in both humans and rodents, it is not completely clear how adipocyte FA oxidation is regulated post-translationally and how it contributes to whole-body energy metabolism in an autonomous manner. In this regard, our preliminary studies provide compelling evidence that a protein encoded by Apolipoprotein 6 (ApoL6) is a selective regulator of mitochondrial trifunctional protein (TFP), the key enzyme catalyzing FA β-oxidation. ApoL6 is highly expressed in WAT and differentiated adipocytes. In contrast, BAT normally expresses low levels of ApoL6, which increases during obesity or thermoneutrality-induced whitening. We found that in the basal condition, ApoL6 is localized to mitochondria, resulting in attenuation of mitochondrial FA oxidation. Transgenic mice expressing ApoL6 in BAT exhibited a lower thermogenic capacity upon cold exposure, and decreased energy expenditure along with increased adiposity. Conversely, adipose ApoL6 knockout mice on HFD showed a decreased body weight and fat mass gain. Based on these preliminary data, we hypothesize that by inhibiting mitochondrial FA oxidation and thereby decreasing energy expenditure, ApoL6 plays a key role in (1) maintaining fat storage in WAT and whole-body energy balance, and (2) impeding non-shivering thermogenesis in whitened BAT. There are three aims: In aim 1, we will determine the mechanistic role of mitochondrially localized ApoL6 in adipocyte FA oxidation by using gain- and loss-of-function cell models. In Aim 2 we will determine how adipose specific ApoL6 ablation in mice affects diet-induced obesity and its related metabolic changes including insulin resistance. In Aim 3 we will use both loss- and gain-of-function mouse models to define the role of ApoL6 in the regulation of BAT thermogenesis during obesity- and thermoneutrality-induced whitening. Evidence derived from this project should provide novel insight into the molecular basis for the regulation of FA oxidation and energy metabolism in adipose tissue, thereby advancing the possibilities for the development of novel therapeutic approaches to combat obesity and type 2 diabetes.
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Characterization of assembly and activation of the Shigella type III secretion injectisome
  • 批准号:
    10535257
  • 项目类别:
  • 资助金额:
    $63.09万
  • 财政年份:
    2022
  • 负责人:
    Jun Liu
  • 依托单位:
Characterization of assembly and activation of the Shigella type III secretion injectisome
  • 批准号:
    10673048
  • 项目类别:
  • 资助金额:
    $61.68万
  • 财政年份:
    2022
  • 负责人:
    Jun Liu
  • 依托单位:
Lipid metabolism and adipose tissue function
  • 批准号:
    10532169
  • 项目类别:
  • 资助金额:
    $50.49万
  • 财政年份:
    2021
  • 负责人:
    Jun Liu
  • 依托单位:
Functional and Structural Analysis of the Dot/Icm Type IVB Secretion Machine
  • 批准号:
    10682410
  • 项目类别:
  • 资助金额:
    $58.63万
  • 财政年份:
    2020
  • 负责人:
    Jun Liu
  • 依托单位:
海外基金