Adipocyte insulin signaling in metabolism and aging

代谢和衰老中的脂肪细胞胰岛素信号传导

• 批准号: 8112522
• 负责人: STEVEN J RUSSELL
• 金额: $ 10.83万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112522
• 关键词: Acetylcysteine; Adipocytes; Adipose tissue; Age; Age-Months; Aging; Alleles; Animals; Antioxidants; Ascorbic Acid; Body Weight decreased; Control Animal; Data; Development; Diabetes Mellitus; Eating; Electron Transport; Endocrine; Energy Metabolism; Fatty Acids; Fatty acid glycerol esters; Genes; Genotype; Glucose; Goals; Health; Human; Insulin; Insulin Receptor; Insulin Resistance; Intake; Interruption; K-Series Research Career Programs; Knock-out; Knockout Mice; Learning; Leptin; Life; Link; Longevity; Measures; Mentors; Metabolic; Metabolism; Mitochondria; Morphology; Mus; Nuclear; Obesity; Oxidative Stress; Oxygen Consumption; Paraquat; Pathway interactions; Phenotype; Production; Proteins; Research; Research Personnel; Resistance; Respiration; Role; Signal Transduction; Specificity; Stress; Testing; Time; Tissues; Toxin; Training; Weaning; Weight; Weight Gain; Work; adipocyte biology; adipokines; adiponectin; biological adaptation to stress; career; cohort; critical developmental period; critical period; emerging adult; enzyme activity; fetal; glucose tolerance; improved; insight; insulin sensitivity; insulin signaling; knockout animal; mature animal; middle age; oxidation; oxidative damage; programs; research study; respiratory

DESCRIPTION (provided by applicant): The objective of Dr. Russell's research is to understand the role of insulin signaling in regulating mammalian lifespan. Fat specific insulin receptor knockout (FIRKO) mice are protected from obesity despite increased food intake, remain insulin sensitive as they age, are resistant to oxidative stress, and have a prolonged lifespan. Dr. Russell will investigate the roles of systemic insulin sensitivity vs. fat specific insulin resistance in the stress resistance and longevity phenotypes of FIRKO mice. He will also investigate the tissue specificity of increased energy expenditure and oxidative stress resistance in FIRKO mice and determine whether they are mechanistically linked. Finally, he will test whether knockout of adipocyte IR in adult animals, rather than during fetal life, will reproduce the beneficial changes seen in FIRKO mice. These studies will provide insight into the mechanisms of stress resistance and longevity in FIRKO mice and will determine whether blocking adipocyte insulin signalling has potential improving human health and longevity. The goal of this Career Development Award is to allow Dr. Russell to establish an independent research program on the role of insulin and adipocyte biology in regulating aging. In addition to the proposed research, he will undertake specialized training in the study of aging. Dr. Ronald Kahn is well suited to sponsor Dr. Russell because of his pioneering work in insulin signalling and his record as a mentor. Dr. Russell's primary focus on aging, rather than insulin signaling and diabetes, will help to distinguish him from his mentor. A committee of distinguished aging experts will assist Dr. Russell in building expertise in the field of aging, provide career guidance, and promote his development into an independent investigator. Lay summary: Permanently blocking the ability of insulin to act on the fat of mice before they are born increases their lifespan and makes them more resistant to certain toxins, while at the same time making them resistant to weight gain and diabetes. The purpose of this study is to learn more about how this occurs, and to determine whether blocking insulin signalling in fat has potential to improve human health and longevity.

描述（由申请人提供）：Russell 博士的研究目的是了解胰岛素信号传导在调节哺乳动物寿命中的作用。脂肪特异性胰岛素受体敲除 (FIRKO) 小鼠尽管食物摄入量增加，但仍能免受肥胖的影响，随着年龄的增长，仍能保持胰岛素敏感性，对氧化应激具有抵抗力，并且寿命更长。 Russell 博士将研究全身胰岛素敏感性与脂肪特异性胰岛素抵抗在 FIRKO 小鼠的应激抵抗和长寿表型中的作用。他还将研究 FIRKO 小鼠能量消耗增加和氧化应激抵抗力增加的组织特异性，并确定它们是否存在机械关联。最后，他将测试成年动物（而不是胎儿期）脂肪细胞 IR 的敲除是否会重现 FIRKO 小鼠中观察到的有益变化。这些研究将深入了解 FIRKO 小鼠的抗应激和长寿机制，并将确定阻断脂肪细胞胰岛素信号传导是否有可能改善人类健康和长寿。 该职业发展奖的目标是让 Russell 博士能够建立一个关于胰岛素和脂肪细胞生物学在调节衰老中的作用的独立研究计划。除了拟议的研究之外，他还将接受衰老研究方面的专门培训。罗纳德·卡恩博士非常适合赞助拉塞尔博士，因为他在胰岛素信号传导方面的开创性工作以及他作为导师的记录。拉塞尔博士主要关注衰老，而不是胰岛素信号和糖尿病，这将有助于将他与他的导师区分开来。由杰出老龄化专家组成的委员会将协助拉塞尔博士建立老龄化领域的专业知识，提供职业指导，并促进他发展成为一名独立研究者。 简单总结：在小鼠出生前永久阻断胰岛素作用于小鼠脂肪的能力，可以延长它们的寿命，并使它们对某些毒素具有更强的抵抗力，同时使它们能够抵抗体重增加和糖尿病。这项研究的目的是更多地了解这种情况是如何发生的，并确定阻断脂肪中的胰岛素信号传导是否有可能改善人类健康和寿命。