Department of Biomedical Engineering and Chemical Engineering, AET 1.102, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX, 78249, USA.
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
Sci Rep. 2021 Mar 8;11(1):5442. doi: 10.1038/s41598-021-84828-z.
Obesity and the metabolic disease epidemic has led to an increase in morbidity and mortality. A rise in adipose thermogenic capacity via activation of brown or beige fat is a potential treatment for metabolic diseases. However, an understanding of how local factors control adipocyte fate is limited. Mice with a null mutation in the laminin α4 (LAMA4) gene (KO) exhibit resistance to obesity and enhanced expression of thermogenic fat markers in white adipose tissue (WAT). In this study, changes in WAT extracellular matrix composition in the absence of LAMA4 were evaluated using liquid chromatography/tandem mass spectrometry. KO-mice showed lower levels of collagen 1A1 and 3A1, and integrins α7 (ITA7) and β1 (ITB1). ITA7-ITB1 and collagen 1A1-3A1 protein levels were lower in brown adipose tissue compared to WAT in wild-type mice. Immunohistochemical staining confirmed lower levels and different spatial distribution of ITA7 in KO-WAT. In culture studies, ITA7 and LAMA4 levels decreased following a 12-day differentiation of adipose-derived stem cells into beige fat, and knock-down of ITA7 during differentiation increased beiging. These results demonstrate that extracellular matrix interactions regulate adipocyte thermogenic capacity and that ITA7 plays a role in beige adipose formation. A better understanding of the mechanisms underlying these interactions can be used to improve systemic energy metabolism and glucose homeostasis.
肥胖和代谢性疾病的流行导致发病率和死亡率的上升。通过激活棕色或米色脂肪来增加脂肪的产热能力，是治疗代谢性疾病的一种潜在方法。然而，人们对于局部因素如何控制脂肪细胞命运的理解是有限的。层粘连蛋白α4（LAMA4）基因缺失的小鼠（KO 型）表现出肥胖的抵抗力和白色脂肪组织（WAT）中米色脂肪标志物的表达增强。在这项研究中，使用液相色谱/串联质谱法评估了缺乏 LAMA4 时 WAT 细胞外基质组成的变化。KO 型小鼠的胶原蛋白 1A1 和 3A1 以及整合素α7（ITA7）和β1（ITB1）水平较低。与野生型小鼠的 WAT 相比，棕色脂肪组织中的 ITA7-ITB1 和胶原蛋白 1A1-3A1 蛋白水平较低。免疫组织化学染色证实 KO-WAT 中的 ITA7 水平较低，且空间分布不同。在培养研究中，脂肪来源干细胞分化为米色脂肪的第 12 天，ITA7 和 LAMA4 水平下降，分化过程中 ITA7 的敲低增加了米色化。这些结果表明细胞外基质相互作用调节脂肪细胞的产热能力，ITA7 在米色脂肪形成中发挥作用。更好地了解这些相互作用的机制可以用于改善全身能量代谢和葡萄糖稳态。
