miR-223 Plays A Key Role in Obesogen-Enhanced Adipogenesis in Mesenchymal Stem Cells and in Transgenerational Obesity

Endocrinology. 2023 Feb 6:bqad027. doi: 10.1210/endocr/bqad027. Online ahead of print.ABSTRACTExposure of pregnant F0 mouse dams to the obesogen tributyltin (TBT) predisposes unexposed male descendants to obesity and diverts mesenchymal stem cells (MSCs) toward the adipocytic lineage. TBT promotes adipogenic commitment and differentiation of MSCs, in vitro. To identify TBT-induced factors predisposing MSCs toward the adipocytic fate, we exposed mouse MSCs to TBT, the PPARγ-selective agonist rosiglitazone or the RXR-selective agonist LG-100268. Then we determined their transcriptomal profiles to determine candidate microRNAs (miR) regulating adipogenic commitment and differentiation. Of the top 10 candidate microRNAs predicted by Ingenuity Pathway Analysis, miR-21, miR-33 and miR-223 were expressed consistent with an ability to differentially regulate target genes during adipogenesis. 24-hour exposure to 50 nM TBT caused miR-223 levels in MSCs to increase; expression of its target genes ZEB1, NFIB, and FOXP1 was decreased. ROSI and TBT increased miR-223 levels. This induction was inhibited by the PPARγ antagonist T0070907 but not by the RXR antagonists HX531 or UVI3003, placing miR-223 downstream of PPARγ. Chromatin immunoprecipitation confirmed TBT-induced binding of PPARγ to regulatory elements in the miR-223 promoter. miR-223 levels were elevated in white adipose tissue of F2 and F3 male descendants of pregnant F0 mouse dams exposed to 50 nM TBT throughout gestation. mi...
Source: Endocrinology - Category: Endocrinology Authors: Source Type: research