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进显著延长了人的平均寿命 在发达国家。随着老年人口的增长，医生们正在治疗更多的 患有与年龄有关的疾病的患者。代谢综合征、动脉粥样硬化的发病率不断上升 疾病、胰岛素抵抗和糖尿病--糖尿病占总人口的比例从7%上升到近20% 75岁--挑战全球医学界。影响胰岛素抵抗的两个有充分证据的因素 糖尿病是缺乏体力活动和不健康的饮食，两者结合起来可能会导致肥胖。 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 长寿。限制卡路里摄入可以减少脂肪的体积，改善胰岛素敏感性，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，艾姆斯矮小和 GHRKO小鼠对注射的胰岛素高度敏感，即使体积增加或正常，也能长期存活 脂肪含量(取决于年龄)。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基因敲除导致白色脂肪有益的改变 影响胰岛素敏感性和寿命的组织。 在拟议的研究中，我们将调查高脂肪饮食(Hfd)和内脏脂肪储备对胰岛素的影响。 正常小鼠、Ames侏儒小鼠和GHRKO小鼠的信号和寿命。我们认为长寿的艾姆斯矮星和 GHRKO小鼠将对HFD的有害影响产生抵抗力。同样基于我们的初步数据显示 在GHRKO和AMES中，内脏脂肪在胰岛素信号调节中的作用截然不同，几乎相反 矮小小鼠与正常动物相比，我们认为去除内脏脂肪不会改善胰岛素 这些长寿突变体的行为和寿命。 我们相信，这些研究将阐明内脏脂肪储备和饮食对胰岛素的相互作用。 信号和长寿。提出了以下具体目标： 目的1：分析手术切除内脏脂肪库和基因对胰岛素的交互作用 GHRKO、Ames侏儒和正常小鼠的信号、脂肪细胞因子、脂代谢和寿命。 目的2：分析高脂饮食(HFD)对胰岛素信号转导、脂肪细胞因子、细胞因子、血脂和胰岛素的影响。 GHRKO、Ames侏儒和正常小鼠的代谢。 目的3：在体内测定无生长激素作用的内脏脂肪对胰岛素信号的作用 通过将GHRKO的内脏脂肪移植到正常小鼠体内。

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

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

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