Introduction and Objective: The accumulation of adipose tissue occurs through adipocyte hypertrophy or adipogenesis, the latter refers to the proliferation and differentiation of adipose progenitor cells (APCs). Starting from middle age, adults often experience a notable increase in visceral adipose tissue mass, known as visceral adiposity, which is closely linked to a series of metabolic disorders. However, the mechanisms by which early aging contributes to adipose tissue accumulation remain poorly understood. Despite the low turnover rate of adipocytes in young mice and adults, we found that adipogenesis is unlocked during middle age and continues into early aging. Specifically, we identified a distinct APC subpopulation—termed committed preadipocytes, age-enriched (CP-As)—which demonstrated high adipogenic capacity in vitro and in vivo. We further identified leukemia inhibitory factor receptor (LIFR) as a functional marker of CP-As and demonstrated that LIFR/STAT3 signaling is essential for their enhanced adipogenesis. This project aims to determine the main ligand for activating CP-A adipogenesis.Methods: CP-As enriched from the stromal vascular fractions isolated from visceral white adipose tissue of mice and humans were subjected to LIFR/STAT3 downstream signal activation and 3D adipogenesis assays while treated with various potential LIFR ligands.Results: We identified leukemia inhibitory factor (LIF) to be the main ligand for activating CP-A adipogenesis. Treating mouse CP-As with LIF significantly increased proliferation and differentiation of these cells into adipocytes in 3D culture. Adding LIF neutralizing antibody or LIFR inhibitor significantly reduced mouse CP-A adipogenesis. LIF treatment also promoted adipogenesis of primary human APCs isolated from middle-aged donors, which was abrogated by LIF neutralizing antibody or LIFR inhibitor.Conclusion: This project provides new mechanistic insights into depot-specific adipose tissue aging and offers therapeutic potential to preserve metabolic healthspan.
J. Han: None. G. Wang: None. A. Song: None. Y. Wang: None. A. Wang: None.
R01AG063854; R01DK142668
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