BACKGROUND Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported. METHODS GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3βADKO and GSK3αADKO). A comprehensive whole-body metabolism analysis was performed on obese GSK3βADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3βADKO and GSK3αADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3βADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition. RESULTS Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER stress in obese AT and improve metabolic disorders associated with obesity. CONCLUSIONS Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity.

中文翻译：

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GSK3β 缺陷扩大了肥胖脂肪脉管系统以减轻代谢紊乱。


背景 在脂肪组织 （AT） 扩张的同时保持发达的血管系统可显着降低代谢并发症的风险。尽管 GSK3β （糖原合酶激酶-3 β） 以其在各种细胞过程中的作用而闻名，但其在 AT 中的特定功能和身体稳态调节尚未见报道。方法 将 GSK3β-floxed 和 GSK3α-floxed 小鼠与脂联素-Cre 小鼠杂交，生成 GSK3β 或 GSK3α 脂肪细胞特异性敲除小鼠 （GSK3βADKO 和 GSK3αADKO）。对高脂饮食诱导的肥胖 GSK3βADKO 小鼠进行全面的全身代谢分析。对肥胖 GSK3βADKO 和 GSK3αADKO 小鼠的 AT 进行 RNA 测序。对肥胖 GSK3βADKO 小鼠的 AT 进行了各种分析，包括血管灌注研究、脂肪分解分析、多重蛋白质测定、体外蛋白质磷酸化测定和整装组织学染色。在缺氧条件下，使用在成熟脂肪细胞的条件培养基中培养的 3B-11 内皮细胞进行成管实验。使用具有 GSK3 抑制的培养脂肪细胞进行染色质沉淀和免疫荧光研究。结果我们的研究结果提供了第一个证据，证明脂肪细胞特异性敲除 GSK3β 扩大了 AT 血管形成并减轻了与肥胖相关的代谢紊乱。脂肪细胞中的 GSK3β 缺陷（而不是 GSK3α）激活 AMPK（AMP 活化蛋白激酶），导致 HIF-2α 的磷酸化和核积累增加，从而增强转录调控。 因此，脂肪细胞增加了 VEGF （血管内皮生长因子） 表达，VEGF 将 VEGFR2 参与内皮细胞，促进血管生成，扩大脉管系统，并改善肥胖 AT 内的血管灌注。GSK3β 缺乏症通过增加胰岛素增敏激素脂联素和保持健康的脂肪细胞功能，促进 AT 重塑，使不健康的脂肪细胞功能转向更健康的状态。这些作用导致肥胖 AT 的纤维化、活性氧和 ER 应激减少，并改善与肥胖相关的代谢紊乱。结论脂肪细胞中 GSK3β 的缺失激活了 AMPK/HIF-2α/VEGF/VEGFR2 轴，促进肥胖 AT 内的脉管系统扩张。这导致局部微环境显着改善，减少炎症并有效改善与肥胖相关的代谢紊乱。