Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Biochim Biophys Acta Mol Cell Res. 2024 Apr;1871(4):119701. doi: 10.1016/j.bbamcr.2024.119701. Epub 2024 Feb 27.
Recent findings suggest that uncarboxylated osteocalcin (GluOC) promotes glucose and lipid metabolism via its putative receptor GPRC6A; however, its direct effect on adipocytes remains elusive. In this study, we elucidated the effects of GluOC on adipocytes, with an emphasis on the role of cell adhesion molecules. We determined that GluOC promoted the expression of adipocyte adhesion molecule (ACAM) and its transcription factor Krüppel-like factor 4 and enhanced the cortical actin filament assembly, which ameliorated lipid droplet hypertrophy. Additionally, GluOC upregulated the expression of integrin αVβ3 and activation of focal adhesion kinase (FAK) and prevented insulin receptor substrate 1 (IRS1) degradation by inhibiting the ubiquitin-proteasome system via the FAK-PLC-PKC axis, which activated IRS1-Akt-mediated glucose transporter 4 (GLUT4) transport. Furthermore, we showed that GluOC elevated the expression of the insulin-independent glucose transporters GLUT1 and GLUT8, which facilitated insulin stimulation-independent glucose transport. The GluOC-induced activation of integrin αVβ3 signaling promoted microtubule assembly, which improved glucose and lipid metabolism via its involvement in intracellular vesicular transport. GluOC treatment also suppressed collagen type 1 formation, which might prevent adipose tissue fibrosis in obese individuals. Overall, our results imply that GluOC promotes glucose and lipid metabolism via ACAM, integrin αVβ3, and GLUT1 and 8 expression, directly affecting adipocytes.
最近的研究结果表明，未羧化骨钙素（GluOC）通过其假定的受体 GPRC6A 促进葡萄糖和脂质代谢；然而，其对脂肪细胞的直接影响仍不清楚。在这项研究中，我们阐明了 GluOC 对脂肪细胞的影响，重点研究了细胞黏附分子的作用。我们发现 GluOC 促进了脂肪细胞黏附分子（ACAM）及其转录因子 Krüppel 样因子 4 的表达，并增强了皮质肌动蛋白丝的组装，从而改善了脂滴肥大。此外，GluOC 上调了整合素 αVβ3 的表达和粘着斑激酶（FAK）的激活，并通过 FAK-PLC-PKC 轴抑制泛素-蛋白酶体系统来防止胰岛素受体底物 1（IRS1）降解，从而激活 IRS1-Akt 介导的葡萄糖转运体 4（GLUT4）转运。此外，我们表明 GluOC 升高了胰岛素非依赖性葡萄糖转运体 GLUT1 和 GLUT8 的表达，这促进了胰岛素刺激非依赖性葡萄糖转运。GluOC 诱导的整合素 αVβ3 信号激活促进了微管组装，通过参与细胞内囊泡运输，改善了葡萄糖和脂质代谢。GluOC 处理还抑制了胶原 1 型的形成，这可能防止肥胖个体的脂肪组织纤维化。总的来说，我们的结果表明，GluOC 通过 ACAM、整合素 αVβ3 和 GLUT1 和 8 的表达促进葡萄糖和脂质代谢，直接影响脂肪细胞。
