Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice

ObjectivePlatelet Derived Growth Factor Receptor Beta (Pdgfr{beta}) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfr{beta} in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. MethodsWe employed Pdgfr{beta} gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfr{beta} activity. ResultsAcute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfr{beta} deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfr{beta} activation in young mice stymied beige fat development. Mechanistically, Pdgfr{beta} deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfr{beta} activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfr{beta} expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfr{beta} restored beige fat formation in obese mice, improving whole-body metabolism. ConclusionThis study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfr{beta} signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfr{beta} as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.