The adipose tissues play crucial roles in regulation of lipid metabolism and overall energy balance. Whilst the white adipose tissue (WAT) sequesters excessive lipids, the brown adipose tissue (BAT) promotes energy expenditure through its ability to breakdown fat and drive thermogenesis. Aging associates with perturbations in lipid metabolism and energy imbalance that lead to the development of the metabolic syndrome. Key features of white adipose aging include decreased lipid storage and impaired lipolysis that promote fat redistribution into visceral compartments. Recent findings indicate the presence of myogenic factor 5-positive (Myf5+) progenitor-derived brown adipocyte-like cells in WAT. Our published studies have shown that this BAT-like remodeling of WAT increases energy expenditure and promotes insulin sensitivity. However, whether aging affects remodeling of WAT into a BAT-like phenotype is largely unclear. Our preliminary studies indicate a key role of autophagy in differentiation of myogenic factor 5-positive (Myf5+) progenitors into BAT, and that loss of autophagy in these progenitors remarkably suppresses BAT-like remodeling of WAT. Autophagy activity decreases with age in diverse cells, and consequently, we propose to examine whether changes in autophagy with age modify remodeling of WAT into BAT-like through effects on Myf5+ progenitors and on immune cells known to modulate tissue remodeling. The main goal of the study is to understand the contribution of autophagy to whole body lipid homeostasis and energy balance by regulating adipose remodeling in young and old organisms. We will: 1) examine whether changes with age in adipocyte lipid metabolism modify the adipose immune cells and autophagy in Myf5+ progenitors; 2) determine the effect of age-related changes in autophagy in adipocytes and Myf5+ progenitors on adipose remodeling; 3) explore the possible beneficial effect on whole body lipohomeostasis and energy balance of anti-aging interventions (using scheduled feeding as a novel approach, and mTOR inhibition) shared with P1, P2 and P3 of this PP, and determine if their effect is by activation of autophagy and adipose remodeling. Relevance: The metabolic syndrome affects greater than 44% of the U.S. population aged more than 50 years. Understanding the mechanisms contributing to perturbed lipid metabolism should be instrumental in developing new therapeutic strategies against the metabolic syndrome of aging. .

Public Health Relevance

The metabolic syndrome is a major health issue that affects greater than 44% of the U.S. population aged more than 50 years. In this application, we will determine whether autophagy decreases in adipocytes and adipose progenitors with age and dietary stress. We will examine how cross talk between autophagy pathways in adipocytes and adipose progenitors promotes brown adipose tissue-like remodeling of white fat, and determine the role of adipose-resident macrophages in this remodeling. We will explore the beneficial effect of anti-aging interventions on adipose remodeling and lipohomeostasis. These studies could lead to development of new therapeutic strategies against the metabolic syndrome of aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Albert Einstein College of Medicine, Inc
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Walters, Ryan O; Arias, Esperanza; Diaz, Antonio et al. (2018) Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans. Cell Rep 25:663-676.e6
Mocholi, Enric; Dowling, Samuel D; Botbol, Yair et al. (2018) Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy. Cell Rep 24:1136-1150
Rodriguez-Muela, Natalia; Parkhitko, Andrey; Grass, Tobias et al. (2018) Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest 128:3008-3023
Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424
Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12
Kaushik, Susmita; Cuervo, Ana Maria (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365-381
Amengual, Jaume; Guo, Liang; Strong, Alanna et al. (2018) Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100. Circ Res 122:568-582
Bejarano, Eloy; Murray, John W; Wang, Xintao et al. (2018) Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell :e12777
Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647
Dowling, Samuel D; Macian, Fernando (2018) Autophagy and T cell metabolism. Cancer Lett 419:20-26

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