The transcription factor NKX1-2 promotes adipogenesis and may contribute to a balance between adipocyte and osteoblast differentiation

Abstract

Although adipogenesis is mainly controlled by a small number of master transcription factors, including CCAAT/enhancer-binding protein family members and peroxisome proliferator-activated receptor ␥ (PPAR␥), other transcription factors also are involved in this process. Thyroid cancer cells expressing a paired box 8 (PAX8)-PPAR␥ fusion oncogene trans-differentiate into adipocyte-like cells in the presence of the PPAR␥ ligand pioglitazone, but this trans-differentiation is inhibited by the transcription factor NK2 homeobox 1 (NKX2-1). Here, we tested whether NKX family members may play a role also in normal adipogenesis. Using quantitative RT-PCR (RT-qPCR), we examined the expression of all 14 NKX family members during 3T3-L1 adipocyte differentiation. We found that most NKX members, including NKX2-1, are expressed at very low levels throughout differentiation. However, mRNA and protein expression of a related family member, NKX1-2, was induced during adipocyte differentiation. NKX1-2 also was up-regulated in cultured murine ear mesenchymal stem cells (EMSCs) during adipogenesis. Importantly, shRNA-mediated NKX1-2 knockdown in 3T3-L1 preadipocytes or EMSCs almost completely blocked adipocyte differentiation. Furthermore, NKX1-2 overexpression promoted differentiation of the ST2 bone marrowderived mesenchymal precursor cell line into adipocytes. Additional findings suggested that NKX1-2 promotes adipogenesis by inhibiting expression of the antiadipogenic protein COUP transcription factor II. Bone marrow mesenchymal precursor cells can differentiate into adipocytes or osteoblasts, and we found that NKX1-2 both promotes ST2 cell adipogenesis and inhibits their osteoblastogenic differentiation. These results support a role for NKX1-2 in promoting adipogenesis and possibly in regulating the balance between adipocyte and osteoblast differentiation of bone marrow mesenchymal precursor cells. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1 and S2 and Table S1.

Influence of the Postmortem/Storage Time of Human Corneas on the Properties of Cultured Limbal Epithelial Cells

“…As shown on Figure 1 D, the expression of all the 50 genes identified was dramatically reduced in the LPM/ST hLECs group. Amongst them, several are known to encode proteins that regulate particularly important epithelial cell functions such as apoptosis ( ST18 , CISD3 ) [ 39 , 40 ], differentiation ( TBR1 , BARX1 , NKX1-2 , FOXB1 , APOL1 , PROP1 , TSACC ) [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], proliferation ( CEBPD , MNX1-AS1 , GPR75 , FZD9 , GAS2L3 , PFKL , TPT1-AS1 , CYP17A1 , MIR22HG ) [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], and migration ( ARHGAP9 , ITGAM , EMILIN1 , ZNF554 , SOX8 ) [ 59 , 60 , 61 , 62 , 63 ]. Moreover, the involvement of some of these genes in the cellular functions listed above was validated further by our IPA analyses.…”

Nkx1.2 deletion decreases fat production in zebrafish

“…The regulation of adipocyte differentiation by Nkx1‐2 is a complex process that involves multiple signaling pathways and transcriptional interactions. According to the model proposed by Chen et al, Nkx1‐2 represses expression of COUP transcription factor 2, which otherwise represses PPARγ and C/EBPα [20]. By repressing COUP transcription factor 2, Nkx1‐2 indirectly promotes the expression of PPARγ and C/EBPα, thereby facilitating adipocyte differentiation.…”

“…Recent studies by Chen et al have shown that Nkx1‐2 may regulate the balance between adipocyte and osteoblast differentiation of ST2 cells (bone marrow‐derived stromal cell) [20]. This suggests a potential role for Nkx1‐2 in adipogenesis, but further in vivo evidence is required to confirm this conclusion.…”

Epigenetic Regulators of White Adipocyte Browning

“…NKX1-2: NK1 homeobox 2, a TF that belongs to the NKX family of proteins, is shown to be induced during 3T3L-1 adipocyte differentiation [ 137 ]. Additionally, shRNA-mediated knockdown of NKX1-2 in 3T3L-1 cells or in-ear MSCs wholly abrogated adipocyte differentiation.…”