Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells

Abstract

The identification of factors that define adipocyte precursor potential has important implications for obesity. Preadipocytes are fibroblastoid cells committed to becoming round lipid-laden adipocytes. In vitro, this differentiation process is facilitated by confluency, followed by adipogenic stimuli. During adipogenesis, a large number of cytostructural genes are repressed before adipocyte gene induction. Here we report that the transcriptional repressor transcription factor 7-like 1 (TCF7L1) binds and directly regulates the expression of cell structure genes. Depletion of TCF7L1 inhibits differentiation, because TCF7L1 indirectly induces the adipogenic transcription factor peroxisome proliferator-activated receptor γ in a manner that can be replaced by inhibition of myosin II activity. TCF7L1 is induced by cell contact in adipogenic cell lines, and ectopic expression of TCF7L1 alleviates the confluency requirement for adipocytic differentiation of precursor cells. In contrast, TCF7L1 is not induced during confluency of non-adipogenic fibroblasts, and, remarkably, forced expression of TCF7L1 is sufficient to commit nonadipogenic fibroblasts to an adipogenic fate. These results establish TCF7L1 as a transcriptional hub coordinating cell-cell contact with the transcriptional repression required for adipogenic competency.A dipose tissue is a highly specialized compartment of cells actively involved in maintaining global metabolic homeostasis through lipid synthesis and storage, adipokine secretion, and insulin responsiveness (1). Adipocytes compose the majority of cells in adipose tissue and play a critical role in normal physiology, but their dysfunction is also at the center of a diverse range of diseases, including obesity, diabetes, and lipodystrophies (2). Furthermore, primary preadipocytes and adipose-derived stem cells have shown promise in treating multiple conditions (3-5). Therefore, it is critical to understand the process by which spindly fibroblastic precursor cells undergo conversion into round lipid-laden fat cells.In vitro models of adipogenesis, such as the extensively studied committed preadipocyte cell line 3T3-L1 cells, have elucidated two major phases of adipogenesis: commitment and terminal differentiation (6, 7). Terminal differentiation is characterized by the induction of metabolic genes, many of which are the direct targets of the transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/CAAT-binding protein (C/ EBP) α and β (8-14). Recent efforts have focused on identifying committed preadipocyte populations in vivo (15, 16), as well as on determining molecular factors that define the committed preadipocytes phenotype. Zinc finger protein 423 (Zfp423) is a critical preadipocyte factor upstream of PPARγ that is not present in non-adipogenic fibroblasts (17). However, Zfp423 also has been identified as a regulator of neurologic development (18), suggesting that other factors also may be involved in specifying adipogenic competency and commitment of precursor cells up...

What We Talk About When We Talk About Fat

“…Zfp423 expression in the developing adipocyte is repressed by the highly related factor Zfp521, which promotes osteogenesis and inhibits adipogenesis through interactions with Ebf1, another transcription factor required for early adipose commitment (Festa et al, 2011; Kang et al, 2012). Tcf7l1 also regulates adipogenic lineage commitment, although it acts in a very different manner, by responding to confluency and mediating changes in structural proteins that regulate differentiation (Cristancho et al, 2011). …”

Regulation of Early Adipose Commitment by Zfp521

“…Our understanding of early events in adipogenesis, however, is relatively underdeveloped. Notably, Zfp423 and Tcf7L1 have been recently proposed to facilitate early determination events in adipogenesis [15]–[17]. Zfp423 is a large and interesting molecule, containing 30 C2H2 Krüppel-like zinc fingers.…”

Epigenetic programming of Dnmt3a mediated by AP2α is required for granting preadipocyte the ability to differentiate

“…A number of reports have revealed that the MDI-induced differentiation is controlled by a complicated network of transcription factors, in which CCAT-enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor- γ (PPAR γ ) have critical roles. 7, 8, 9, 10, 11 Although some previous studies reported a few factors such as transcriptional factor 7-like 1, GATA-2 and GATA-3 that were involved in adipogenic competency during the CI stage, 12, 13, 14 the factors that function for regulation of adipogenesis in the CI stage are largely unknown.…”