Adipose Development: From Stem Cell to Adipocyte

Abstract

Cell culture models have been developed to study commitment and subsequent differentiation of preadipocytes into adipocytes. Bone morphogenetic protein 4 commits mesenchymal stem cells to the adipose lineage. Other factors, including Wnt signaling, cell density, and cell shape, play a role in lineage commitment. Following commitment to the adipose lineage, growth-arrested preadipocytes can differentiate to adipocytes by treatment with insulin-like growth factor 1, glucocorticoid and an agent that increases cAMP level. This process is characterized by a rapid and transient increase in CCAAT/enhancer binding protein (C/EBP) beta and synchronous re-entry into the cell cycle. Acquisition of DNA-binding by C/EBPbeta occurs after the transcription factor becomes phosphorylated. The cells enter a growth-arrested state and begin terminal differentiation. C/EBPalpha, peroxisome proliferator-activated receptor gamma, and adipocyte determination, and differentiation-dependent factor 1 coordinate the expression of genes that create and maintain the adipocyte phenotype.

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

“…To further investigate the molecular mechanisms underlying the inhibitory effect of PGF2a on adipocyte differentiation, we next examined the effects of PGF2a on the expression of the C/EBPb, PPARg, and C/EBPa transcription factors that are known to play a critical role in the regulation of adipogenesis [Rosen and Spiegelman, 2000;Otto et al, 2005]. As shown in Figure 5A, treatment of cells with PGF2a alone had no effect on the MDI-induced expression of the early transcription factor C/EBPb.…”

“…These fibroblast-like cells are committed to the adipocyte lineage and can be induced to efficiently differentiate into morphologically distinct, lipid-ladened, mature adipocytes following exposure to a adipogenic hormonal cocktail comprising of methylisobu-tylxanthine (Mix: a phosphodiesterase inhibitor that elevates intracellular cAMP levels), the glucocorticoid dexamesthasone (Dex) and insulin (collectively known as MDI). As a result of extensive studies largely using this in vitro model system, it is now established that the pathway of terminal adipocyte differentiation is a highly coordinated process that proceeds via the sequential induction of a cascade of transcription factors, including the peroxisome proliferator-activated receptor g (PPARg) and members of the CCAAT/enhancer-binding protein (C/EBP) family [Rosen and Spiegelman, 2000;Otto et al, 2005]. When exposed to MDI, growth-arrested preadipocytes first re-enter the cell cycle and undergo several rounds of cell division known as mitotic clonal expansion (MCE) [Tang et al, 2003], during which time they upregulate the expression of the early transcription factors C/EBPb and C/EBPd [Yeh et al, 1995;Wu et al, 1996].…”

“…When exposed to MDI, growth-arrested preadipocytes first re-enter the cell cycle and undergo several rounds of cell division known as mitotic clonal expansion (MCE) [Tang et al, 2003], during which time they upregulate the expression of the early transcription factors C/EBPb and C/EBPd [Yeh et al, 1995;Wu et al, 1996]. C/EBPb and C/ EBPd then bind directly to cognate-binding sites in the proximal promoters of the PPARg and C/EBPa genes and promote the expression of these two proadipogenic transcription factors [Rosen and Spiegelman, 2000;Otto et al, 2005]. Once expressed, PPARg and C/EBPa re-enforce each other's expression in an autoregulatory loop and then act coordinately to direct the expression of a panel of adipocyte-specific genes that result in the specification of the terminally differentiated mature adipocyte phenotype [Rosen and Spiegelman, 2000;Otto et al, 2005].…”

“…C/EBPb and C/ EBPd then bind directly to cognate-binding sites in the proximal promoters of the PPARg and C/EBPa genes and promote the expression of these two proadipogenic transcription factors [Rosen and Spiegelman, 2000;Otto et al, 2005]. Once expressed, PPARg and C/EBPa re-enforce each other's expression in an autoregulatory loop and then act coordinately to direct the expression of a panel of adipocyte-specific genes that result in the specification of the terminally differentiated mature adipocyte phenotype [Rosen and Spiegelman, 2000;Otto et al, 2005].…”

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

“…A number of transcription factors are known to be activated during adipocyte differentiation. A prominent transcription factor family is the CCAAT/enhancer binding protein (C/EBP) family (Otto and Lane, 2005). C/EBPalpha and C/EBPbeta are members of the family of six functionally and structurally related basic leucine zipper DNA binding proteins.…”