Benvie Abigail M, Berry Daniel C
Division of Nutritional Sciences, Cornell University Ithaca, NY 14853 USA.
bioRxiv. 2024 Jun 18:2024.06.17.599436. doi: 10.1101/2024.06.17.599436.
Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ 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.
We employed Pdgfrβ 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 Pdgfrβ activity.
Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.
This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ 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 Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.
血小板衍生生长因子受体β（Pdgfrβ）抑制衰老哺乳动物中冷诱导米色脂肪细胞的形成。我们旨在确定在衰老小鼠中删除Pdgfrβ是否能通过激活2型固有淋巴细胞（ILC2）使代谢活跃的米色脂肪细胞恢复活力，以及这种效应是否能抵消饮食诱导的肥胖相关米色脂肪减少。
我们采用了针对米色脂肪前体细胞（APC）的Pdgfrβ功能获得和功能丧失小鼠模型。我们的方法包括冷暴露、代谢笼分析以及年龄和饮食诱导的肥胖模型，以研究在不同Pdgfrβ活性下米色脂肪的发育和代谢功能。
单独急性冷暴露可增强衰老小鼠的代谢益处，与米色脂肪生成无关。然而，衰老小鼠中Pdgfrβ的缺失重新建立了代谢功能正常的米色脂肪细胞的形成，增强了新陈代谢。相反，年轻小鼠中Pdgfrβ的组成型激活阻碍了米色脂肪的发育。机制上，Pdgfrβ的缺失上调了IL-33，促进了ILC2的募集和激活，而Pdgfrβ的激活降低了IL-33水平并抑制了ILC2活性。值得注意的是，饮食诱导的肥胖显著增加了Pdgfrβ表达和Stat1信号传导，抑制了IL-33诱导和ILC2激活。Pdgfrβ的基因缺失恢复了肥胖小鼠中米色脂肪的形成，改善了全身代谢。
本研究表明，仅冷暴露就能触发衰老哺乳动物的代谢激活。然而，逆转衰老和肥胖小鼠中的Pdgfrβ信号不仅能恢复米色脂肪的形成，还能恢复代谢功能并增强白色脂肪组织（WAT）的免疫环境。这些发现突出了Pdgfrβ作为对抗与年龄和肥胖相关的代谢衰退的治疗策略的关键靶点。
