Wang Li, Li Jiajia, Tang Ping, Zhu Dongliang, Tai Lixin, Wang Yuan, Miyata Tsukiko, Woodgett James R, Di Li-Jun
Department of Biomedical Sciences, Faculty of Health Sciences (L.W., J.L., P.T., D.Z., L.T., Y.W., L.D.), University of Macau, China.
The Ministry of Education Frontiers Science Center for Precision Oncology (L.W., L.D.), University of Macau, China.
Circ Res. 2025 Jan 3;136(1):91-111. doi: 10.1161/CIRCRESAHA.124.325187. Epub 2024 Dec 4.
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.
GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3β and GSK3α). A comprehensive whole-body metabolism analysis was performed on obese GSK3β mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3β and GSK3α 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 GSK3β 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.
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 (endoplasmic reticulum) stress in obese AT and improve metabolic disorders associated with obesity.
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.
在脂肪组织（AT）扩张的同时维持发达的血管系统可显著降低代谢并发症的风险。尽管糖原合酶激酶-3β（GSK3β）在各种细胞过程中的作用已为人所知，但其在脂肪组织中的具体功能以及对身体稳态的调节尚未见报道。
将GSK3β基因敲除小鼠和GSK3α基因敲除小鼠与脂联素-Cre小鼠杂交，以产生GSK3β或GSK3α脂肪细胞特异性敲除小鼠（GSK3β和GSK3α）。对高脂饮食诱导的肥胖GSK3β小鼠进行全面的全身代谢分析。对肥胖GSK3β和GSK3α小鼠的脂肪组织进行RNA测序。对肥胖GSK3β小鼠的脂肪组织进行了各种分析，包括血管灌注研究、脂解分析、多重蛋白质检测、体外蛋白质磷酸化检测和全组织学染色。使用在缺氧条件下成熟脂肪细胞的条件培养基中培养的3B-11内皮细胞进行管形成实验。使用GSK3抑制的培养脂肪细胞进行染色质沉淀和免疫荧光研究。
我们的研究结果首次证明，脂肪细胞特异性敲除GSK3β可扩大脂肪组织血管化并减轻肥胖相关的代谢紊乱。脂肪细胞中GSK3β的缺失而非GSK3α的缺失激活了AMPK（AMP激活的蛋白激酶），导致HIF-2α的磷酸化增加和核积累，从而增强转录调控。因此，脂肪细胞增加了血管内皮生长因子（VEGF）的表达，该因子与内皮细胞上的VEGFR2结合，促进血管生成，扩大血管系统，并改善肥胖脂肪组织内的血管灌注。GSK3β的缺失促进脂肪组织重塑，通过增加胰岛素增敏激素脂联素并保持健康脂肪细胞功能，将不健康的脂肪细胞功能转变为更健康的状态。这些作用导致肥胖脂肪组织中的纤维化、活性氧和内质网应激减少，并改善与肥胖相关的代谢紊乱。
脂肪细胞中GSK3β的缺失激活了AMPK/HIF-2α/VEGF/VEGFR2轴，促进肥胖脂肪组织内的血管系统扩张。这导致局部微环境显著改善，减少炎症并有效改善与肥胖相关的代谢紊乱。
