Dietary fat, visceral fat depots and aging

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。在上个世纪，医疗保健的改善大大提高了发达国家的平均寿命。随着老年人口的增长，医生正在治疗越来越多的患有与年龄有关的疾病的病人。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从75岁以上人口的7%上升到近20%，这给全球医学界带来了挑战。影响胰岛素抵抗和糖尿病的两个有充分证据的因素是缺乏体育活动和不健康的饮食，两者加在一起可能导致肥胖。几项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。限制卡路里可以减少脂肪的体积，提高胰岛素敏感性，延长寿命。人们可以推断，苗条的身体可以促进健康的胰岛素作用和更长的寿命。然而，Ames侏儒和GHRKO小鼠对注射胰岛素都非常敏感，尽管脂肪量增加或正常（取决于年龄），但它们都很长寿。是什么调节了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敲除导致白色脂肪组织的有益改变，从而影响胰岛素敏感性和寿命。在拟建的研究中，我们将研究高脂肪饮食（HFD）和内脏脂肪储存对正常小鼠、Ames侏儒小鼠和GHRKO小鼠胰岛素信号传导和寿命的影响。我们认为长寿的Ames侏儒和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侏儒小鼠中调节胰岛素信号传导的作用非常不同，几乎相反，我们提出内脏脂肪去除不会改善这些长寿突变体的胰岛素作用和寿命。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。目的1：分析手术切除内脏脂肪库和基因型对GHRKO、Ames侏儒和正常小鼠胰岛素信号、脂肪细胞因子、脂质代谢和寿命的相互作用。目的2：分析高脂饮食（HFD）对GHRKO、Ames侏儒和正常小鼠胰岛素信号、脂肪细胞因子、细胞因子、脂质和代谢的影响。目的3：通过将GHRKO的内脏脂肪移植到正常小鼠体内，确定体内生长激素对胰岛素信号没有作用时内脏脂肪的功能。

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.