Metabolic consequences of adipocyte progenitor replicative senescence: mechanism and intervention

点击翻译按钮获取中文摘要

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.