Functional characterization of adipocyte-derived lipocalin 2-containing extracellular vesicles in senescence

About This Grant

PROJECT SUMMARY Maintaining healthy adipose tissue function is essential for metabolic homeostasis and the prevention of metabolic diseases. As potent endocrine cells, adipocytes secret various bioactive molecules and extracellular vesicles that influence the function of tissues and organs throughout the body. Besides adipocytes, multipotent stem and progenitor cells in adipose tissue are crucial for tissue maintenance and repair throughout life. With aging, adipose tissue undergoes species-conserved changes, including decreased subcutaneous adiposity, increased visceral adiposity, and a decline in the thermogenic capacity of brown and beige adipose tissue. In contrast to the detrimental effects of adipocyte hypertrophy, hyperplasia, a process known as adipogenesis, supports tissue development, repair, and metabolic health. However, adipogenesis is impaired during aging, which has been linked to adipose progenitor cell senescence, potentially contributing to the development of metabolic diseases. Recent studies indicate that extracellular vehicles (EVs), particularly adipocyte-derived EVs (Ad-EVs) play a role in intercellular communication within adipose tissue, regulating its function. Ad-EVs exhibit heterogeneity, with large and small Ad-EVs differing in protein and lipid composition, suggesting functional diversity. However, the specific subtypes of Ad-EVs secreted by adipocytes and their distinct roles in local and systemic metabolic regulation remain unexplored. Our preliminary studies indicate that Lipocalin 2 (LCN2), a novel phosphatidic acid (PA) binding protein, plays a potential role in senescence and adipogenesis of adipose stem and progenitor cells (ASPCs) through EV-mediated intercellular communication. Lcn2 deficiency impairs adipogenesis and results in hypertrophic obesity. Stromal- vascular (SV) cells from the brown and white adipose tissue of Lcn2 knockout mice exhibit increased senescence and decreased adipogenesis. Importantly, we have identified LCN2 in a distinct subpopulation of Ad-EVs that is separate from adiponectin-containing Ad-EVs. In this proposal, we aim to characterize the cargo composition and function of LCN2-containing EVs (LCN2+EVs) released from adipocytes, examining their role in ASPC senescence and adipogenesis during aging. We hypothesize that adipocyte-derived LCN2+EVs possess anti-senescence properties that maintain ASPC health and adipogenic capacity through adipocyte-to-ASPC communication within adipose tissue, and this effect is context-dependent. We propose two aims to characterize the cargo composition of LCN2+EVs released from adipocytes upon metabolic and inflammatory stress, and 2) determine the role of adipocyte-derived LCN2+EVs in ASPC senescence and adipogenesis during aging. The project outcomes are expect to provide new perspectives on the pathogenesis of aging-related metabolic disorders and pave the way for developing new therapeutic strategies targeting adipose tissue function.