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

Abstract

Exposure 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. miR-223 levels were potentiated in males fed with an increased fat diet. We infer that TBT induced miR-223 expression and increased adipogenesis in MSCs through the PPARγ pathway and that transgenerationally increased expression of miR-223 plays an important role in the development of obesity caused by TBT exposure.

Kawakawa tea Intake and its anti-diabetic and anti-inflammatory effects: An integrative microRNA and mRNA analysis

“…On the other hand, the decreased abundance of hsa-miR-223-3p could be attributed to the decreased expression of PPARγ. PPARγ is identi ed as a direct regulator of this miRNA in adipose tissue [45]. Given this study's ndings of reduced abundance of both PPARγ and hsa-miR-223-3p following kawakawa tea intake, it remains to be clari ed whether kawakawa tea has a modulatory impact on in ammation and related pathways by in uencing the hsa-miR-223-3p/PPARγ axis.…”

Inherited Epigenetic Hallmarks of Childhood Obesity Derived from Prenatal Exposure to Obesogens

“…In this regard, it has been described that the dysregulation of lncRNA (long non-coding RNA) involved in glucose homeostasis such as Gm6277 or Gm10804 as well as in adipose accumulation (Rian) can persist up to the F4 male generation [ 64 ]. Similarly, miR-223, a key mediator of PPARγ-dependent macrophage alternative activation, was found to be overexpressed in F2 and F3 male descendants of TBT-exposed dams [ 65 ].…”

The Regulatory Role of MicroRNAs in Obesity and Obesity-Derived Ailments

“…For example, Du and colleagues in 2020 [36] hypothesized that in mice, betaine, a natural compound commonly present in beet, shellfish, spinach, Swiss chard, and other leafy green vegetables [36], can interact with gut microbiota-derived miR-378a and improve obesity since the miR-378a family acts as a regulator of numerous metabolic pathways, including autophagy and mitochondrial metabolism [53]. Likewise, more recently, Chen and collaborators (2022) [47] investigated the response of miR-143 in the presence of betaine in lipid metabolism. In wild-type mouse liver, it was observed that the expression of miR-143 was downregulated when betaine was supplemented.…”

“…In wild-type mouse liver, it was observed that the expression of miR-143 was downregulated when betaine was supplemented. Also, the supplementation with betaine and miR-143 knockout caused obesity attenuation due to the repression of the glycoprotein nonmetastatic melanoma protein B (GPNMB), which has been reported to promote lipogenesis in white adipose tissue (WAT) and intensify diet-induced obesity [47,54]. Furthermore, fatty acid synthase (FASN) was upregulated when miR-143 was knocked out; nevertheless, FASN was observed to be downregulated when miR-143 knockout was supplemented with betaine.…”

“…These mechanisms ultimately lead to a relevant reduction in fat proportion in the body weight as well as better energy consumption. Hence, miR-143 knockout, supplemented with betaine, could be a novel therapy for obesity management [47].…”