Division of Nutritional Sciences, Cornell University Ithaca, NY 14853, USA.
Division of Nutritional Sciences, Cornell University Ithaca, NY 14853, USA.
Mol Metab. 2024 Nov;89:102028. doi: 10.1016/j.molmet.2024.102028. Epub 2024 Sep 13.
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）抑制老年哺乳动物冷诱导的米色脂肪形成。我们旨在确定在老年小鼠中删除 Pdgfrβ 是否可以通过激活 2 型固有淋巴细胞（ILC2）来重新激活代谢活跃的米色脂肪细胞，以及这种效应是否可以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祖细胞（APCs）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肥胖模型，以检查不同 Pdgfrβ 活性下米色脂肪的发育和代谢功能。
单独急性冷暴露增强了老年小鼠的代谢益处，而与米色脂肪生成无关。然而，在老年小鼠中删除 Pdgfrβ 重新建立了代谢功能米色脂肪细胞的形成，增强了代谢。相反，在年轻小鼠中组成性激活 Pdgfrβ 抑制了米色脂肪的发育。从机制上讲，Pdgfrβ 缺失上调了 IL-33，促进了 ILC2 的募集和激活，而 Pdgfrβ 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 的表达和 Stat1 信号传导，从而抑制了 IL-33 的诱导和 ILC2 的激活。Pdgfrβ 的遗传缺失恢复了肥胖小鼠的米色脂肪形成，改善了全身代谢。
这项研究表明，单独的冷温度暴露就可以触发老年哺乳动物的代谢激活。然而，在老年和肥胖小鼠中逆转 Pdgfrβ 信号不仅恢复了米色脂肪的形成，而且恢复了代谢功能并增强了白色脂肪组织（WAT）的免疫环境。这些发现强调了 Pdgfrβ 是对抗与年龄和肥胖相关的代谢衰退的治疗策略的关键靶标。
