Endocrine regulation of metabolic health during aging

摘要 衰老与新陈代谢健康的进行性下降有关，并代表着 导致2型糖尿病、心血管疾病和 老年非酒精性脂肪性肝病。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，可能涉及内在变化 在组织代谢和组织间代谢的扰动串扰。内分泌 因子在调节碳水化合物和脂肪代谢中起着关键作用 维持全身能量平衡。内分泌信号的扰动是 通常在哺乳动物的衰老过程中观察到。然而，内分泌信号的性质 在哺乳动物衰老过程中控制代谢动态平衡的基因仍然没有明确的定义。在……里面 初步研究表明，神经调节蛋白4(NRG4)是一种新的脂肪细胞来源 保护小鼠免受胰岛素抵抗和肝脏脂肪堆积的分泌因子 一种依赖年龄的方式。NRG4在小鼠脂肪组织中的表达 因卡路里限制而升高。这些发现构成了我们中心假设的基础 通过脂肪因子传递的内分泌信号在保存 衰老过程中的代谢动态平衡。在这项建议中，我们计划评估 该因子在年龄相关代谢调节中的生理作用 功能丧失的小鼠模型。我们将描绘其在衰老过程中的调控并探索 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.