Dietary fat, visceral fat depots and aging

膳食脂肪、内脏脂肪库和衰老

基本信息

批准号：
8149819
负责人：
MICHAL Mateusz MASTERNAK
金额：
$ 28.16万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8149819
关键词：
Adipocytes Adipose tissue Affect Age Aging Animals Body Weight Body fat Caloric Restriction Communities Data Developed Countries Diabetes Mellitus Diet Dietary Fats Disease Elderly Environment Excision Fatty acid glycerol esters Food Genetic Genotype Glucose Goals Growth Hormone Receptor Healthcare Human Incidence Infiltration Insulin Insulin Resistance Knock-out Knockout Mice Laboratories Life Life Style Liver Longevity Medical Metabolic syndrome Mus Mutation Obesity Operative Surgical Procedures Organ Pathology Patients Perception Physical activity Physicians Population Predisposition Production Publishing Race Rattus Regimen Regulation Research Resistance Review Literature Role Siblings Signal Transduction Skeletal Muscle Testing Tissues Transplantation Visceral Work adiponectin age related base cytokine diabetic fasting glucose glucose tolerance improved in vivo insulin sensitivity insulin signaling lipid metabolism mutant public health relevance research study response somatotropin-binding protein subcutaneous

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our research is to determine the effects of visceral fat on insulin sensitivity and longevity. Improvements in healthcare during the last century have significantly increased the average lifespan in developed countries. With the growing population of elderly, physicians are treating a greater number of patients suffering from age-related diseases. Growing incidence of metabolic syndrome, atherosclerotic disease, insulin resistance and diabetes mellitus-which jumps from 7% to almost 20% of the population after age 75-challenges the global medical community. Two well-documented factors affecting insulin resistance and diabetes are a lack of physical activity and an unhealthy diet, which may cause obesity when combined. Several studies with mice and rats indicated that obesity causes insulin resistance and has negative effects on longevity. Calorie restriction decreases the volume of fat, improves insulin sensitivity and extends longevity. One could infer that a lean body promotes healthy insulin action and a longer life. However, Ames dwarf and GHRKO mice are both hyper-sensitive to injected insulin and long-lived despite an increased or normal volume of fat (depending on age). What regulates high insulin sensitivity and longer lifespan in these mutant animals? We hypothesize that Prop1df mutation and GHR knockout cause beneficial alterations in white adipose tissue that influences insulin sensitivity and longevity. In the proposed studies, we will investigate effects of a high fat diet (HFD) and visceral fat depots on insulin signaling and longevity in normal, Ames dwarf and GHRKO mice. We propose that long-living Ames dwarf and GHRKO mice will be resistant to the detrimental effects of HFD. Also based on our preliminary data indicating a very different, nearly opposite role of visceral fat in the regulation of insulin signaling in GHRKO and Ames dwarf mice in comparison to normal animals, we propose that visceral fat removal will not improve insulin action and longevity of these long-lived mutants. We believe that these studies will elucidate the interaction of visceral fat depots and diet on insulin signaling and longevity. The following specific aims are proposed: Aim 1: Analyze the interactive effects of surgical removal of visceral fat depots and genotype on insulin signaling, adipocytokines, lipid metabolism and longevity in GHRKO, Ames dwarf and normal mice. Aim 2: Analyze the effects of a high fat diet (HFD) on insulin signaling, adipocytokines, cytokines, lipid and metabolism in GHRKO, Ames dwarf and normal mice. Aim 3: Determine the function of visceral fat developed in the absence of GH action on insulin signaling in vivo by transplanting visceral fat from GHRKO into normal mice. PUBLIC HEALTH RELEVANCE: Identifying the mechanisms and/or causes of extended longevity and delayed aging is one of the great scientific challenges of the 21st century. Do these mechanisms involve genetics, lifestyle or dietary choices? If one could identify the mechanisms involved, future research would have targets to extend lifespan and improve the "healthspan" of the human race.

描述（由申请人提供）：我们研究的长期目标是确定内脏脂肪对胰岛素敏感性和寿命的影响。上个世纪医疗保健的进步显着延长了发达国家的平均寿命。随着老年人口的不断增加，医生正在治疗越来越多患有与年龄相关疾病的患者。代谢综合征、动脉粥样硬化性疾病、胰岛素抵抗和糖尿病的发病率不断上升，在 75 岁之后从 7% 跃升至近 20%，这对全球医学界提出了挑战。缺乏体力活动和不健康饮食是影响胰岛素抵抗和糖尿病的两个有据可查的因素，这两个因素结合在一起可能会导致肥胖。几项针对小鼠和大鼠的研究表明，肥胖会导致胰岛素抵抗，并对寿命产生负面影响。热量限制可以减少脂肪体积，提高胰岛素敏感性并延长寿命。人们可以推断，瘦身可以促进健康的胰岛素作用并延长寿命。然而，艾姆斯侏儒小鼠和 GHRKO 小鼠都对注射的胰岛素高度敏感，并且尽管脂肪量增加或正常（取决于年龄），但它们的寿命却很长。是什么调节这些突变动物的高胰岛素敏感性和更长的寿命？我们假设 Prop1df 突变和 GHR 敲除会导致白色脂肪组织发生有益的改变，从而影响胰岛素敏感性和寿命。在拟议的研究中，我们将研究高脂肪饮食 (HFD) 和内脏脂肪库对正常小鼠、艾姆斯侏儒小鼠和 GHRKO 小鼠的胰岛素信号传导和寿命的影响。我们认为长寿的艾姆斯侏儒小鼠和 GHRKO 小鼠将能够抵抗 HFD 的有害影响。此外，我们的初步数据表明，与正常动物相比，内脏脂肪在 GHRKO 和 Ames 侏儒小鼠的胰岛素信号调节中的作用非常不同，几乎相反，我们认为去除内脏脂肪不会改善这些小鼠的胰岛素作用和寿命。长寿突变体。我们相信这些研究将阐明内脏脂肪库和饮食对胰岛素信号和寿命的相互作用。提出以下具体目标：目标 1：分析手术切除内脏脂肪库和基因型对 GHRKO、艾姆斯侏儒小鼠和正常小鼠的胰岛素信号、脂肪细胞因子、脂质代谢和寿命的交互影响。目标 2：分析高脂饮食 (HFD) 对 GHRKO、Ames 侏儒小鼠和正常小鼠的胰岛素信号、脂肪细胞因子、细胞因子、脂质和代谢的影响。目标 3：通过将 GHRKO 的内脏脂肪移植到正常小鼠体内，确定在 GH 对胰岛素信号传导不存在作用的情况下形成的内脏脂肪的功能。公共卫生相关性：确定延长寿命和延缓衰老的机制和/或原因是 21 世纪的重大科学挑战之一。这些机制是否涉及遗传、生活方式或饮食选择？如果能够确定所涉及的机制，未来的研究将有延长寿命和改善人类“健康寿命”的目标。