Dietary fat, visceral fat depots and aging

膳食脂肪、内脏脂肪库和衰老

• 批准号: 8720641
• 负责人: MICHAL Mateusz MASTERNAK
• 金额: $ 28.06万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720641
• 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; research study; response; somatotropin-binding protein; subcutaneous

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.

我们研究的长期目标是确定内脏脂肪对胰岛素敏感性和 长寿。上个世纪医疗保健的改善已大大提高了平均寿命 在发达国家。随着老年人人数不断增长，医生正在治疗更多 患有与年龄有关的疾病的患者。代谢综合征，动脉粥样硬化的发生率不断增长 在 年龄75岁 - 全球医学界。两个影响胰岛素耐药性的有据可查的因素 糖尿病缺乏体育锻炼和不健康的饮食，这可能会在合并时会导致肥胖。 对小鼠和大鼠的几项研究表明，肥胖症会引起胰岛素抵抗，并对 长寿。卡路里限制会减少脂肪的量，提高胰岛素敏感性并延长寿命。 可以推断瘦身可以促进健康的胰岛素作用和更长的寿命。但是，艾姆斯矮人和 GHRKO小鼠对注射的胰岛素高敏感，尽管体积增加或正常 脂肪（取决于年龄）。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敲除在白色脂肪中引起有益的改变 影响胰岛素敏感性和寿命的组织。 在拟议的研究中，我们将研究高脂肪饮食（HFD）和内脏脂肪库对胰岛素的影响 正常的信号传导和寿命，Ames矮人和Ghrko小鼠。我们提出了悠久的艾姆斯矮人和 GHRKO小鼠将抵抗HFD的有害作用。也基于我们指示的初步数据 内脏脂肪在GHRKO和AMES中的胰岛素信号传导调节中的一个截然不同的，几乎相反的作用 矮小鼠与普通动物相比，我们提出，内脏脂肪去除不会改善胰岛素 这些长寿突变体的作用和寿命。 我们认为这些研究将阐明内脏脂肪库和饮食在胰岛素上的相互作用 信号和寿命。提出了以下具体目标： 目标1：分析内脏脂肪库外科手术去除和基因型对胰岛素的互动效果 Ghrko，Ames矮小和正常小鼠的信号传导，脂肪细胞因子，脂质代谢和寿命。 目标2：分析高脂饮食（HFD）对胰岛素信号传导，脂肪细胞因子，细胞因子，脂质和 Ghrko，Ames矮小和正常小鼠的代谢。 AIM 3：确定在没有GH作用对体内胰岛素信号传导的情况下开发的内脏脂肪的功能 通过将内脏脂肪从GHRKO移植到正常小鼠中。

项目成果

Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age.

• DOI: 10.1007/s11357-015-9765-1
• 发表时间: 2015-06-01
• 期刊: Age (Dordrecht, Netherlands)
• 作者: Hill, Cristal M;Arum, Oge;Bartke, Andrzej
• 通讯作者: Bartke, Andrzej

RasGrf1: genomic imprinting, VSELs, and aging.

• DOI: 10.18632/aging.100354
• 发表时间: 2011-07
• 期刊: Aging
• 作者: Ratajczak MZ;Kucia M;Liu R;Shin DM;Bryndza E;Masternak MM;Tarnowski M;Ratajczak J;Bartke A
• 通讯作者: Bartke A

The Role of Ames Dwarfism and Calorie Restriction on Gut Microbiota.

艾姆斯侏儒症和热量限制对肠道微生物群的作用。

• DOI: 10.1093/gerona/glz236
• 发表时间: 2020
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Wiesenborn,DeniseS;Gálvez,EricJC;Spinel,Lina;Victoria,Berta;Allen,Brittany;Schneider,Augusto;Gesing,Adam;Al-Regaiey,KhalidA;Strowig,Till;Schäfer,Karl-Herbert;Masternak,MichalM
• 通讯作者: Masternak,MichalM

Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse.

• DOI: 10.1111/acel.12373
• 发表时间: 2015-12
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Victoria B;Dhahbi JM;Nunez Lopez YO;Spinel L;Atamna H;Spindler SR;Masternak MM
• 通讯作者: Masternak MM

Non-homologous end joining induced alterations in DNA methylation: A source of permanent epigenetic change.

• DOI: 10.18632/oncotarget.16122
• 发表时间: 2017-06-20
• 期刊: Oncotarget
• 作者: Allen B;Pezone A;Porcellini A;Muller MT;Masternak MM
• 通讯作者: Masternak MM