Metabolic consequences of adipocyte progenitor replicative senescence: mechanism and intervention

在能量过剩的情况下，未被身体利用的脂肪酸通常储存在白色脂肪细胞中， 在那里，它们可以被释放出来，在其他器官耗尽能量的情况下用作燃料。在肥胖中，脂肪细胞 白色脂肪组织(AT)的增大(肥大)导致AT包含甘油三酯的能力降低， 导致其他器官的脂肪沉积，从而导致胰岛素抵抗(IR)和2型糖尿病(T2D) 发展。如果AT血管化良好且由小的白色脂肪细胞组成，肥胖不会导致T2D 和富含线粒体的米色脂肪细胞，表明AT增殖是代谢健康的关键。脂肪细胞 在整个衰老过程中经历周转，他们在AT中的池由异质脂肪前体维持 在AT中分裂、自我更新和分化为前体脂肪细胞以取代死亡脂肪细胞的细胞(APC)。我们的 初步数据显示，APC的增殖受到昼夜节律的控制，这在高脂饮食的情况下是不受调控的。 喂食。血小板衍生生长因子受体、血小板衍生生长因子受体α和血小板衍生生长因子受体β，它们发出信号，引导血管生成细胞分化为米色或白色 脂肪细胞似乎分别参与了这种昼夜的增殖。与端粒缩短相关的临床数据 T2D研究表明，APC持续分裂并产生新的脂肪细胞的能力， 而不是依赖于先前存在的巨大的白色脂肪细胞的扩张，解释了T2D的缺乏 “健康肥胖”个体的发展。这项建议是基于初步数据显示，长期- APC复制性衰老和耗竭的长期结局是脂肪细胞肥大和AT纤维化，结果 代谢功能障碍。我们的主要假设是APC在AT中过度增殖，并因饮食- 诱导肥胖和昼夜有丝分裂信号中断，加速APC复制衰老，导致 到AT代谢功能障碍和2TD。在这里，我们将使用遗传小鼠模型来分析和操作APC 受pdgf-A/pdgfrα、偏向于米色脂肪生成的信号和APC调控，受 血小板衍生生长因子-D/血小板衍生生长因子受体β，偏向于白色脂肪生成。使用加速端粒的小鼠模型 简而言之，我们将建立白色和米色前脂肪细胞在 AT和综合生理学。在目标2中，使用昼夜节律失调的小鼠模型，我们将研究 控制白色和米色脂肪细胞前体细胞增殖的机制及昼夜节律的影响 AT功能上的APC中断。在目标3中，我们将测试白色和米色APC的营养控制方法 精疲力竭和代谢功能障碍。饮食干预对促有丝分裂信号、APC增殖、 将分析端粒缩短、白色/米色脂肪细胞池和新陈代谢。本研究的一个创新之处 是对不同AT仓库中APC种群如何因新陈代谢而耗尽的机械解释 失衡易导致代谢功能障碍。建立营养途径使APC正常化 核扩散将在肥胖、糖尿病和老龄化领域产生转化影响。

Under conditions of energy excess, fatty acids not utilized by the body are normally stored in white adipocytes, where they can be released and used for fuel under energy depletion by other organs. In obesity, adipocyte enlargement (hypertrophy) in white adipose tissue (AT) leads to a reduced ability of AT to contain triglycerides, causing lipid deposition in other organs, which leads to insulin resistance (IR), and type-2 diabetes (T2D) development. Obesity does not cause T2D if AT is well vascularized and composed of small white adipocytes and mitochondria-rich beige adipocytes, indicating that AT hyperplasia is the key to metabolic health. Adipocytes undergo turnover throughout aging and their pools in AT are maintained by heterogeneous adipose progenitor cells (APCs) that divide, self-renew and differentiate into preadipocytes to replace dying adipocytes in AT. Our preliminary data show that APC proliferation is under circadian control that is dysregulated upon high fat-diet feeding. PDGF receptors, PDGFRα and PDGFRβ, which signal to direct APC differentiation into beige or white adipocytes, respectively, appear to mediate this diurnal proliferation. Clinical data linking telomere shortening in AT with T2D development suggests that sustained ability of APCs to divide and give rise to new adipocytes, rather than reliance on the expansion of previously existing large, white adipocytes, explains the lack of T2D development in “healthy obese” individuals. This proposal is based on preliminary data showing that the long- term outcome of replicative APC senescence and depletion is adipocyte hypertrophy and AT fibrosis, resulting in metabolic dysfunction. Our overarching hypothesis is that APC over-proliferation in AT, aggravated by diet- induced obesity and disruption of circadian mitogenic signaling, accelerates APC replicative senescence, leading to AT metabolic dysfunction and 2TD. Here we will use genetic mouse models to analyze and manipulate APCs regulated by PDGF-A / Pdgfrα, signaling, which are skewed toward beige adipogenesis, and APCs regulated by PDGF-D / Pdgfrβ , which are skewed toward white adipogenesis. Using mouse models of accelerated telomere shortening, we will establish the consequences of replicative senescence of white and beige preadipocytes on AT and integrative physiology. In Aim 2, using mouse models of circadian dysregulation, we will investigate the mechanisms controlling white and beige adipocyte progenitor proliferation and determine the effect of circadian disruption in APC on AT function. In Aim 3, we will test approaches to nutritional control of white and beige APC exhaustion and metabolic dysfunction. Effects of dietary interventions on mitogenic signaling, APC proliferation, telomere shortening, white / beige adipocyte pools and metabolism will be analyzed. An innovation of this study is a mechanistic explanation to how depletion of APC populations in distinct AT depots due to metabolic disbalance predisposes to metabolic dysfunction. Establishing nutritional approaches to normalizing APC proliferation will have a translational impact in the field of obesity, diabetes, and aging.