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， 在其他器官能量耗尽的情况下，它们可以被释放并用作燃料。肥胖时，脂肪细胞 白色脂肪组织 (AT) 增大（肥大）导致 AT 含有甘油三酯的能力降低， 引起其他器官的脂质沉积，从而导致胰岛素抵抗 (IR) 和 2 型糖尿病 (T2D) 发展。如果 AT 血管化良好且由白色小脂肪细胞组成，则肥胖不会导致 T2D 以及富含线粒体的米色脂肪细胞，表明 AT 增生是代谢健康的关键。脂肪细胞 在整个衰老过程中经历更新，并且它们在 AT 中的池由异质脂肪祖细胞维持 分裂、自我更新并分化为前脂肪细胞以取代 AT 中垂死脂肪细胞的细胞 (APC)。我们的 初步数据表明，APC 增殖受到昼夜节律控制，在高脂肪饮食时会失调 喂养。 PDGF 受体、PDGFRα 和 PDGFRβ，发出信号引导 APC 分化为米色或白色 脂肪细胞似乎分别介导了这种昼夜增殖。与端粒缩短相关的临床数据 AT 与 T2D 的发展表明 APC 具有持续分裂和产生新脂肪细胞的能力， 而不是依赖于先前存在的大型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。该提议基于初步数据，表明长期 复制性 APC 衰老和耗竭的最终结果是脂肪细胞肥大和 AT 纤维化，从而导致 在代谢功能障碍中。我们的首要假设是 AT 中 APC 过度增殖，饮食会加剧这种情况 诱导的肥胖和昼夜节律有丝分裂信号的破坏，加速 APC 复制衰老，导致 AT 代谢功能障碍和 2TD。在这里我们将使用基因小鼠模型来分析和操作APC 受 PDGF-A / Pdgfrα 信号传导调节，偏向于米色脂肪生成，APC 受以下调节 PDGF-D / Pdgfrβ ，偏向于白色脂肪生成。使用加速端粒的小鼠模型 缩短时间，我们将确定白色和米色前脂肪细胞复制性衰老对 AT 和综合生理学。在目标 2 中，我们将使用昼夜节律失调的小鼠模型来研究 控制白色和米色脂肪细胞祖细胞增殖的机制并确定昼夜节律的影响 APC 对 AT 功能的破坏。在目标 3 中，我们将测试白色和米色 APC 的营养控制方法 疲劳和代谢功能障碍。饮食干预对有丝分裂信号、APC 增殖、 将分析端粒缩短、白色/米色脂肪细胞池和代谢。本研究的一个创新点 是对不同 AT 库中 APC 群体如何因代谢而耗尽的机制解释 失衡容易导致代谢功能障碍。建立 APC 正常化的营养方法 增殖将对肥胖、糖尿病和衰老领域产生转化影响。

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.