Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY: Cold temperature (<15°C) exposure stimulates perivascular beige adipocyte progenitor cells (bAPCs) to generate beige adipocytes. Beige adipocytes act as cellular furnaces to burn blood glucose and free fatty acids to generate heat. Recent studies have shown the metabolic benefits of beige adipocytes, suggesting potential clinical efficacy for obese patients and type 2 diabetics. However, the potential to form cold-induced beige adipocytes declines with age, creating a pivotal challenge to the therapeutic promise for older individuals, many of whom constitute the obesity epidemic. Our studies begin to unravel how aging suppresses beige adipogenic potential and identifies new ways to rejuvenate beige fat cell biogenesis to restore metabolic fitness in aged mammals. Our previous studies have linked cellular senescence, a state of cellular arrest, of bAPCs to the age- associated decline in beige adipose tissue. In an attempt to find additional mechanisms blocking beige fat biogenesis in aged mammals, we found that the expression and signaling of platelet derived growth factor receptor beta (Pdgfrß) is increased in aged bAPCs. Moreover, ablation of Pdgfrß within the beige adipose lineage restored beige adipocyte generation and improved metabolic health in aged (not young) mice. Despite beige fat formation in aged Pdgfrß-deficient mice, lineage-tracing studies revealed that auxiliary source(s) generated beige adipocytes. In agreement, senescence tests demonstrated that Pdgfrß neither promoted nor reversed cellular senescence. Instead, we found that Pdgfrß signaling prevents group 2 innate lymphoid cell (ILC2) recruitment and activation within iWAT depots. Mechanistically, we identified that Pdgfrß elicits signals via Stat1 to suppress the ILC2-inducer, interleukin-33 (IL-33), to control WAT ILC2 activity. Finally, we identify sympathetic tone as a significant regulator of age-induced Pdgfrß expression. Our aims will elucidate the physiological and cellular role of Pdgfrß in regulating beige fat biogenesis under aging and obese conditions. We will elucidate the Pdgfrß-Stat1 signaling mechanism in bAPCs to control ILC2 recruitment via IL-33. We uncover how sympathetic output regulates Pdgfrß expression to drive the age-dependent beige adipogenic failure. These findings will implicate Pdgfrß signaling as a central node in the bAPC aging process. Importantly, this application will identify factors that reverse age-dependent beige adipogenic failure with a direct clinical utility to combat excess body fat and metabolic dysfunction to extend lifespan and restore health.
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