Endocrine regulation of metabolic health during aging

摘要 衰老与代谢健康的逐步下降有关， 2型糖尿病、心血管疾病的独特风险因素， 老年人非酒精性脂肪肝与年龄相关的生物学基础 代谢性疾病可能是多方面的，从概念上讲，可能涉及内在的变化 组织代谢和组织间代谢串扰的扰动。内分泌 因子在调节碳水化合物和脂质代谢中起关键作用， 维持全身能量平衡内分泌信号的扰动 在哺乳动物衰老过程中常见。然而，内分泌信号的性质 在哺乳动物衰老过程中控制代谢稳态的机制仍然不清楚。在 在初步研究中，我们鉴定了Neuregulin 4（Nrg 4）作为一种新的脂肪细胞来源的 分泌因子，保护小鼠免受胰岛素抵抗和肝脏脂肪积累， 依赖年龄的方式。Nrg4在小鼠脂肪组织中的表达， 通过热量限制而升高。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在保护 衰老过程中的代谢平衡在本提案中，我们计划评估 该因子在年龄依赖性代谢调节中的生理作用， 功能丧失小鼠模型。我们将描述其在衰老过程中的调节，并探索 所涉及的分子和代谢机制。

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.