Autophagy and Adipose tissue Remodeling in Aging (Project 4)

Project Summary 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. .