Endocrine regulation of metabolic health during aging

衰老过程中代谢健康的内分泌调节

• 批准号: 9277806
• 负责人: Jiandie D Lin
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277806
• 关键词: Address; Adipocytes; Adipose tissue; Age; Age of Onset; Age-Months; Aging; Attenuated; Binding; Biological Assay; Biology; Body Composition; Caloric Restriction; Cardiovascular Diseases; Deterioration; Development; Elderly; Endocrine; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Exhibits; Family; Fatty Liver; Fatty acid glycerol esters; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; Hyperlipidemia; Incidence; Insulin Resistance; Knockout Mice; Life Expectancy; Ligands; Light; Liver; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolism; Molecular; Morbidity - disease rate; Mus; Nature; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Physiological; Physiology; Plasma; Play; Regulation; Risk; Risk Factors; Role; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; adipokines; age related; carbohydrate metabolism; design; energy balance; extracellular; feeding; glucose tolerance; improved; lipid metabolism; loss of function; member; mortality; mouse model; neuregulin-4; non-alcoholic fatty liver; novel; protective effect

ABSTRACT Aging is associated with a progressive decline of metabolic health and represents a unique risk factor for the development of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease in the elderly. The biology underlying age-related metabolic disease is likely multifaceted, and conceptually, may involve intrinsic changes in tissue metabolism and perturbations of inter-tissue metabolic crosstalk. Endocrine factors play a critical role in modulating carbohydrate and lipid metabolism and maintaining systemic energy homeostasis. Perturbations of endocrine signaling are commonly observed during mammalian aging. However, the nature of endocrine signals that govern metabolic homeostasis during mammalian aging remains poorly defined. In preliminary studies, we identified Neuregulin 4 (Nrg4) as a novel adipocyte-derived secreted factor that protects mice from insulin resistance and hepatic fat accumulation in an age-dependent manner. The expression of Nrg4 in mouse adipose tissues was elevated by caloric restriction. These findings form the basis for our central hypothesis that endocrine signaling by adipokines plays a uniquely important role in preserving metabolic homeostasis during aging. In this proposal, we plan to evaluate the physiological role of this factor in age-dependent metabolic regulation using gain- and loss-of-function mouse models. We will delineate its regulation during aging and explore the molecular and metabolic mechanisms involved.

抽象的 衰老与代谢健康的逐渐下降有关，代表 开发2型糖尿病，心血管疾病和 老年人的非酒精性脂肪肝病。生物学与年龄有关的生物学 代谢疾病可能是多方面的，并且从概念上讲可能涉及内在变化 在组织代谢和组织间代谢串扰的扰动中。内分泌 因素在调节碳水化合物和脂质代谢以及 维持全身能量稳态。内分泌信号的扰动是 通常在哺乳动物衰老期间观察到。但是，内分泌信号的性质 在哺乳动物衰老期间，控制代谢稳态的定义仍然很差。在 初步研究，我们确定神经蛋白4（NRG4）是一种新型脂肪细胞衍生的 分泌的因素，可保护小鼠免受胰岛素抵抗和肝脂肪的积累 与年龄有关的方式。 NRG4在小鼠脂肪组织中的表达为 通过热量限制提升。这些发现构成了我们中心假设的基础 脂肪因子的内分泌信号传导在保存中起着独特的重要作用 衰老期间的代谢稳态。在此提案中，我们计划评估 该因素在年龄依赖性代谢调节中的生理作用，使用增益和 功能丧失的鼠标模型。我们将在衰老期间描述其法规 涉及的分子和代谢机制。