Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator–activated receptor γ (PPARγ) during adipocyte differentiation

Adipocyte differentiation is thought to involve sequential induction of the transcription factors C/EBPbeta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBPalpha. C/EBPalpha expression is both necessary and sufficient for adipocyte differentiation. Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta induces PPARgamma expression and adipogenesis and that retinoic acid (RA) completely inhibits adipogenesis by either form of C/EBP. In studies of normal preadipocytes, RA does not prevent C/EBPbeta induction but blocks induction of PPARgamma, C/EBPalpha, and adipogenesis. In transient transfection studies, liganded RA receptor (RAR) specifically blocks transcriptional activation by either C/EBPalpha or C/EBPbeta. These results strongly suggest that C/EBPalpha substitutes for C/EBPbeta to induce adipocyte differentiation and that liganded RAR inhibits adipogenesis by blocking C/EBPbeta-mediated induction of downstream genes.

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The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors

Molecular and Cellular Biology ◽

10.1128/mcb.00685-09 ◽

2009 ◽

Vol 30 (3) ◽

pp. 613-625 ◽

Cited By ~ 57

Author(s):

Toshio Maekawa ◽

Wanzhu Jin ◽

Shunsuke Ishii

Keyword(s):

Transcription Factors ◽

Adipocyte Differentiation ◽

Physiological Role ◽

Bone Morphogenetic Protein 2 ◽

Peroxisome Proliferator ◽

Necrosis Factor Alpha ◽

Peroxisome Proliferator Activated Receptor ◽

P38 Inhibitor ◽

Morphogenetic Protein

ABSTRACT ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor γ2 (PPARγ2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-α) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment.

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Transcriptional and Epigenomic Regulation of Adipogenesis

Molecular and Cellular Biology ◽

10.1128/mcb.00601-18 ◽

2019 ◽

Vol 39 (11) ◽

Cited By ~ 36

Author(s):

Ji-Eun Lee ◽

Hannah Schmidt ◽

Binbin Lai ◽

Kai Ge

Keyword(s):

Transcription Factors ◽

Adipocyte Differentiation ◽

Metabolic Diseases ◽

Future Research ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Future Research Directions ◽

Epigenomic Regulation ◽

Adipocyte Development

ABSTRACT Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master “adipogenic” transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.

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Interaction between GATA and the C/EBP Family of Transcription Factors Is Critical in GATA-Mediated Suppression of Adipocyte Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.25.2.706-715.2005 ◽

2005 ◽

Vol 25 (2) ◽

pp. 706-715 ◽

Cited By ~ 156

Author(s):

Qiang Tong ◽

Judy Tsai ◽

Guo Tan ◽

Gökhan Dalgin ◽

Gökhan S. Hotamisligil

Keyword(s):

Transcription Factors ◽

Leucine Zipper ◽

Adipocyte Differentiation ◽

Protein Complexes ◽

Constitutive Expression ◽

Peroxisome Proliferator ◽

Basic Leucine Zipper ◽

Peroxisome Proliferator Activated Receptor ◽

Gata Factors ◽

Direct Binding

ABSTRACT We have previously demonstrated that GATA-2 and GATA-3 are expressed in adipocyte precursors and control the preadipocyte-to-adipocyte transition. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor γ (PPARγ) promoter and suppression of its basal activity. In the present study, we demonstrate that both GATA-2 and GATA-3 form protein complexes with CCAAT/enhancer binding protein α (C/EBPα) and C/EBPβ, members of a family of transcription factors that are integral to adipogenesis. We mapped this interaction to the basic leucine zipper domain of C/EBPα and a region adjacent to the carboxyl zinc finger of GATA-2. The interaction between GATA and C/EBP factors is critical for the ability of GATA to suppress adipocyte differentiation. Thus, these results show that in addition to its previously recognized function in suppressing PPARγ transcriptional activity, interaction of GATA factors with C/EBP is necessary for their ability to negatively regulate adipogenesis.

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Regulation of Peroxisome Proliferator-Activated Receptor γ Expression by Adipocyte Differentiation and Determination Factor 1/Sterol Regulatory Element Binding Protein 1: Implications for Adipocyte Differentiation and Metabolism

Molecular and Cellular Biology ◽

10.1128/mcb.19.8.5495 ◽

1999 ◽

Vol 19 (8) ◽

pp. 5495-5503 ◽

Cited By ~ 294

Author(s):

Lluis Fajas ◽

Kristina Schoonjans ◽

Laurent Gelman ◽

Jae B. Kim ◽

Jamila Najib ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Adipocyte Differentiation ◽

Binding Protein ◽

Regulatory Element ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Pparγ Expression

ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor implicated in adipocyte differentiation and insulin sensitivity. We investigated whether PPARγ expression is dependent on the activity of adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with both adipocyte differentiation and cholesterol homeostasis. Ectopic expression of ADD-1/SREBP-1 in 3T3-L1 and HepG2 cells induced endogenous PPARγ mRNA levels. The related transcription factor SREBP-2 likewise induced PPARγ expression. In addition, cholesterol depletion, a condition known to result in proteolytic activation of transcription factors of the SREBP family, induced PPARγ expression and improved PPRE-driven transcription. The effect of the SREBPs on PPARγ expression was mediated through the PPARγ1 and -3 promoters. Both promoters contain a consensus E-box motif that mediates the regulation of the PPARγ gene by ADD-1/SREBP-1 and SREBP-2. These results suggest that PPARγ expression can be controlled by the SREBP family of transcription factors and demonstrate new interactions between transcription factors that can regulate different pathways of lipid metabolism.

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Calcineurin Mediates the Calcium-dependent Inhibition of Adipocyte Differentiation in 3T3-L1 Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m207913200 ◽

2002 ◽

Vol 277 (51) ◽

pp. 49776-49781 ◽

Cited By ~ 74

Author(s):

Joel W. Neal ◽

Neil A. Clipstone

Keyword(s):

Transcription Factors ◽

Adipocyte Differentiation ◽

Ectopic Expression ◽

Calcium Ionophore ◽

Peroxisome Proliferator ◽

Inhibitory Peptide ◽

Peroxisome Proliferator Activated Receptor ◽

Calcium Dependent ◽

Dependent Inhibition ◽

Calcineurin Activity

Recent studies have revealed that the calcium-dependent serine/threonine phosphatase calcineurin mediates the effects of intracellular calcium in many different cell types. In this study we investigated the role of calcineurin in the regulation of adipocyte differentiation. We found that the specific calcineurin inhibitors cyclosporin A and FK506 overcame the antiadipogenic effect of calcium ionophore on the differentiation of 3T3-L1 preadipocytes. This finding suggests that calcineurin is responsible for mediating the previously documented Ca2+-dependent inhibition of adipogenesis. We further demonstrate that the expression of a constitutively active calcineurin mutant potently inhibits the ability of 3T3-L1 cells to undergo adipocyte differentiation by preventing expression of the proadipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). This calcineurin-mediated block in adipocyte differentiation is rescued by ectopic expression of PPARγ1. Finally, we demonstrate that inhibition of endogenous calcineurin activity with either FK506 or a specific calcineurin inhibitory peptide enhances differentiation of 3T3-L1 cells in response to suboptimal adipogenic stimuli, suggesting that endogenous calcineurin activity normally sets a signaling threshold that antagonizes efficient adipocyte differentiation. Collectively, these data indicate that calcineurin acts as a Ca2+-dependent molecular switch that negatively regulates commitment to adipocyte differentiation by preventing the expression of critical proadipogenic transcription factors.

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The Impact of Anthocyanins and Iridoids on Transcription Factors Crucial for Lipid and Cholesterol Homeostasis

International Journal of Molecular Sciences ◽

10.3390/ijms22116074 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6074

Author(s):

Maciej Danielewski ◽

Agnieszka Matuszewska ◽

Adam Szeląg ◽

Tomasz Sozański

Keyword(s):

Transcription Factors ◽

Cholesterol Metabolism ◽

Binding Protein ◽

Regulatory Element ◽

Cholesterol Homeostasis ◽

Lipid Lowering ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Cell Functions ◽

The Impact

Nutrition determines our health, both directly and indirectly. Consumed foods affect the functioning of individual organs as well as entire systems, e.g., the cardiovascular system. There are many different diets, but universal guidelines for proper nutrition are provided in the WHO healthy eating pyramid. According to the latest version, plant products should form the basis of our diet. Many groups of plant compounds with a beneficial effect on human health have been described. Such groups include anthocyanins and iridoids, for which it has been proven that their consumption may lead to, inter alia, antioxidant, cholesterol and lipid-lowering, anti-obesity and anti-diabetic effects. Transcription factors directly affect a number of parameters of cell functions and cellular metabolism. In the context of lipid and cholesterol metabolism, five particularly important transcription factors can be distinguished: liver X receptor (LXR), peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα) and sterol regulatory element-binding protein 1c (SREBP-1c). Both anthocyanins and iridoids may alter the expression of these transcription factors. The aim of this review is to collect and systematize knowledge about the impact of anthocyanins and iridoids on transcription factors crucial for lipid and cholesterol homeostasis.

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