![]() ![]() Generally, cellular senescence is characterized by a state of cellular arrest and the acquisition of a secreted pro-inflammatory program that targets neighboring cell types, thereby disrupting tissue homeostasis 24, 25. The functional decline in tissue maintenance and function is often due to stem cell or progenitor ageing or senescence 23. Moreover, the mechanisms driving age-dependent beige adipogenic failure is not entirely understood 22. The beiging process, markedly, begins to fail in humans as early as their mid-30’s, creating a significant clinical challenge for the therapeutic promise of beige adipose, especially within the ageing obese population 20. Yet, overriding the prospective health benefits of thermogenic tissue is the inability to generate cold-induced beige adipocytes with age 19, 20, 21. For instance, changes in the abundance of alternatively activated macrophages and group 2 innate lymphoid cells (ILC2s) have been shown to potentially regulate catecholamine levels and APC proliferation and differentiation, respectively, driving beige fat formation and activity 15, 16, 17, 18. In particular, cold exposure can invoke alterations in WAT immune cell composition, which have been suggested to coordinate beige fat development 15, 16, 17, 18. In addition to beige adipocyte recruitment, cold temperatures also facilitate WAT remodeling, which can induce changes in adipocyte size, vascularization, and cellular composition 14. Conversely, lowering the amount or activity of thermogenic fat can predispose rodents, and potentially humans, to metabolic dysregulation in response to a positive energy balance 13. Consistent with this notion, augmenting the number of beige adipocytes or their activity promotes a healthy metabolic profile (i.e., reducing adiposity and lowering blood sugar and fats) in lean mammals 12. Once generated, beige adipocytes futilely burn circulating glucose and free fatty acids to generate heat, an effect that could counteract WAT expansion and improve metabolism 9, 10, 11. ![]() For example, in response to cold temperature exposure, WAT resident perivascular smooth muscle-like adipocyte progenitor cells (APCs) undergo beige adipocyte development 7, 8. Hence, finding inherent mechanisms to burn excess energy to avert age-associated WAT growth could be exploited to attenuate these pathologies and to rejuvenate systemic metabolism in ageing individuals. Central to the obesity epidemic is the uncontrolled expansion and accumulation of white adipose tissue (WAT), which can foster type 2 diabetes, cardiometabolic diseases, and chronic inflammation 2, 3, 4, 5, 6. Mammalian ageing is accompanied by an increased occurrence in obesity and metabolic dysfunction, shortening longevity and hindering the quality of life 1. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals. Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5. We show that genetically deleting Pdgfrβ, in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta ( Pdgfrβ) to prevent beige adipogenesis. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. ![]()
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