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To elucidate the effects of switching a PGF2α agonist, bimatoprost acid (BIM-A), to an EP2 agonist (Omidenepag—OMD; butaprost—Buta) or reversing the switching on adipose tissue, two-dimensional (2D) and three-dimensional (3D) cultures of 3T3-L1 cells were analyzed by lipid staining and according to the mRNA expression of adipogenesis-related genes (<i>Pparγ, Ap2</i>, and <i>Leptin</i>), components of the extracellular matrix (ECM; <i>collagen1</i> (<i>Col1</i>), <i>Col4</i>, <i>Col6</i>, and <i>fibronectin</i> (<i>Fn</i>)), and the sizes and stiffness of the 3D spheroids. Switching from BIM-A to EP2 agonists caused (1) suppression of lipid staining and downregulation of most adipogenesis-related genes, (2) smaller and stiffer 3D spheroids, and (3) upregulation of <i>Col1</i> and <i>Fn</i>, downregulation of <i>Col4</i> (2D), or up-regulation of all ECM genes (3D, BIM-A to OMD), as well as downregulation of <i>Col6</i> (3D, BIM-A to Buta). In contrast, reversing the switching resulted in (1) an enhancement in lipid staining (2D) and a significant upregulation of adipogenesis-related genes (2D, 3D Buta to BIM-A), (2) larger and slightly stiffer 3D spheroids, and (3) upregulation of <i>Col1</i> and <i>Fn</i> (2D). These collective findings indicate that the switching orders of BIM-A and EP2 agonists have a significant effect on lipid metabolism, ECM expression, and the physical stiffness of 3T3-L1 cells.