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MicroRNA-140 Regulates PDGFRα and Is Involved in Adipocyte Differentiation

ABSTRACT: In recent years, the studies of the role of microRNAs in adipogenesis and adipocyte development and the corresponding molecular mechanisms have received great attention. In this work, we investigated the function of miR-140 in the process of adipogenesis and the molecular pathways involved, and we found that adipogenic treatment promoted the miR-140-5p RNA level in preadipocytes. Over-expression of miR-140-5p in preadipocytes accelerated lipogenesis along with adipogenic differentiation by transcriptional modulation of adipogenesis-linked genes. Meanwhile, silencing endogenous miR-140-5p dampened adipogenesis. Platelet-derived growth factor receptor alpha (PDGFRα) was shown to be a miR-140-5p target gene. miR-140-5p over-expression in preadipocyte 3T3-L1 diminished PDGFRα expression, but silencing of miR-140-5p augmented it. In addition, over-expression of PDGFRα suppressed adipogenic differentiation and lipogenesis, while its knockdown enhanced these biological processes of preadipocyte 3T3-L1. Altogether, our current findings reveal that miR-140-5p induces lipogenesis and adipogenic differentiation in 3T3-L1 cells by targeting PDGFRα, therefore regulating adipogenesis. Our research provides molecular targets and a theoretical basis for the treatment of obesity-related metabolic diseases.

SUBMITTER: Yan Y

PROVIDER: S-EPMC9271708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe limited options to treat obesity and its complications result from an incomplete understanding of the underlying molecular mechanisms regulating white adipose tissue development, including adipocyte hypertrophy (increase in size) and hyperplasia (increase in number through adipogenesis). We recently demonstrated that lack of the adaptor protein Nck1 in mice is associated with reduced adiposity and impaired adipocyte differentiation. In agreement, Nck1 depletion in 3 T3-L1 cells also attenuates adipocyte differentiation by enhancing PDGFRα activation and signaling. This is accompanied by higher expression of PDGF-A, a specific PDGFRα ligand, that may contribute to enhanced activation of PDGFRα signaling in the absence of Nck1 in white adipose tissue. However, whether Nck1 deficiency also impairs adipogenic differentiation in bone marrow still remains to be determined.MethodsTo address this point, Nck1-deficient derived bone marrow mesenchymal stem/stromal cells (BM-MSCs) and C3H10T1/2 mesenchymal stem cells were differentiated into adipocytes in vitro. Genes and proteins expression in these cellular models were determined using qPCR and western blotting respectively. Pharmacological approaches were used to assess a role for Nrf2 in mediating Nck1 deficiency effect on mesenchymal stem cells adipocyte differentiation.ResultsNck1 deficiency in both BM-MSCs and C3H10T1/2 results in impaired adipocyte differentiation, accompanied by increased activation of the transcription factor Nrf2, as shown by increased mRNA levels of Nrf2 target genes, including PDGF-A. Using pharmacological activator and inhibitor of Nrf2, we further provide evidence that Nrf2 is an important player in PDGFRα signaling that mediates expression of PDGF-A and impaired adipogenesis in Nck1-deficient BM-MSCs and C3H10T1/2 cells.ConclusionThis study demonstrates that Nck1 deficiency in mesenchymal stem cells impairs adipogenesis through activation of the PDGFRα-Nrf2 anti-adipogenic signaling pathway. Video Abstract.

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MicroRNA-140 Regulates PDGFRα and Is Involved in Adipocyte Differentiation

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