Regulation of Adipocyte Development

Cornelius, Peter; MacDougald, Ormond A.; Lane, M. Daniel

doi:10.1146/annurev.nu.14.070194.000531

Cited by 594 publications

(283 citation statements)

References 78 publications

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“…Finally, DEXA scan analysis revealed that adipose tissues in EPAS1 knockout mice are smaller than those in control mice. 2 Consequently, EPAS1 appears to play a role in promotion of adipose differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…A rapid and transient increase in transcription and expression of C/EBP␤ and C/EBP␦ is observed in the early stages of differentiation. These factors have been shown to promote adipogenesis, presumably through induction of C/EBP␣ and PPAR␥2 (2)(3)(4). The enforced expression of PPAR␥2 or C/EBP␣ has been shown to stimulate adipogenesis in NIH 3T3 fibroblasts (6 -8), suggesting the essential roles played by these factors in regulating adipogenesis in vitro.…”

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confidence: 99%

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EPAS1 Promotes Adipose Differentiation in 3T3-L1 Cells

Shimba

Wada

Hara

et al. 2004

Journal of Biological Chemistry

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Adipose differentiation is regulated by several transcription factors, such as the CAAT/enhancer-binding protein family and peroxisome proliferator activator (PPAR) ␥2. Several recent studies have shown that the basic helix-loop-helix-PAS superfamily is also involved in the regulation of adipose differentiation. In this study, we investigated the roles played by EPAS1 (endothelial PAS domain protein 1) in adipogenesis. EPAS1, also referred to as hypoxia-inducible factor 2␣, is a transcription factor known to play essential roles in catecholamine homeostasis, vascular remodeling, and the maintenance of reactive oxygen species, and so forth. During adipose differentiation in 3T3-L1 cells, the level of EPAS1 mRNA began to increase 6 days after the induction, and EPAS1 was highly expressed in differentiated cells. To examine whether EPAS1 is involved in adipogenesis, we first isolated stable clones from 3T3-L1 cells in which we could induce the expression of an EPAS1 C-terminal deletion mutant (designated EPAS1-(1-485)) with the insect hormone. The induction of EPAS1-(1-485) allowed the cells to accumulate only minimum amounts of intracellular lipid droplets. Consistent with the morphological observations, a minimum amount of aP2 and PPAR␥2 mRNA was induced in the EPAS1-(1-485) cells. We then examined whether or not EPAS1 was able to promote adipogenesis in NIH 3T3 cells, a relatively nonadipogenic cell line. Overexpression of EPAS1 in NIH 3T3 cells induced a significant amount of lipid accumulation compared with that of the control cells in the presence of the PPAR␥ ligand. The results were also confirmed by measuring the expression of adipocyte-related genes. Adenovirus-mediated EPAS1-(1-485) expression resulted in the reduction of basal and insulin-dependent glucose transport in 3T3-L1 adipocytes. The mechanism involved the transcriptional regulation of GLUT1, GLUT4, and IRS3 expression by EPAS1. Taken together, these results suggest that EPAS1 plays several supporting roles in maintaining specific aspects of adipogenesis and adipocyte function including regulation of glucose uptake followed by lipid synthesis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

EPAS1 Promotes Adipose Differentiation in 3T3-L1 Cells

Shimba

Wada

Hara

et al. 2004

Journal of Biological Chemistry

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“…This hyperplasia is mimicked by the adipogenic differentiation program of 3T3-L1 preadipocytes. Treatment of growth-arrested 3T3-L1 preadipocytes with differentiation inducers initiates mitotic clonal expansion (MCE) before expression of genes that give rise to the adipocyte phenotype (3)(4)(5). Whether MCE is a prerequisite for terminal differentiation remains controversial (6), because definitive proof is lacking.…”

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confidence: 99%

Mitotic clonal expansion: A synchronous process required for adipogenesis

Tang

Otto

Lane

2002

Proc. Natl. Acad. Sci. U.S.A.

728

654

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When induced to differentiate, growth-arrested 3T3-L1 preadipocytes synchronously reenter the cell cycle and undergo mitotic clonal expansion (MCE) followed by expression of genes that produce the adipocyte phenotype. The preadipocytes traverse the G1͞S checkpoint synchronously as evidenced by the expression͞ activation of cdk2-cyclin-E͞A, turnover of p27͞kip1, hyperphosphorylation of Rb, translocation of cyclin D1 from nuclei to cytoplasm and GSK-3␤ from cytoplasm to nuclei, and incorporation of [ 3 H]thymidine into DNA. As the cells cross the G1͞S checkpoint, C͞EBP␤ acquires DNA-binding activity, initiating a cascade of transcriptional activation that culminates in the expression of adipocyte proteins. The mitogen-activated protein kinase͞extra-cellular signal-regulated kinase kinase (MEK) inhibitor PD98059 delays, but does not block, MCE and differentiation, the extent of the delay causing a comparable delay in the expression of cell-cycle markers, MCE, and adipogenesis. The more potent and specific MEK inhibitor UO126 and the cyclin-dependent kinase inhibitor roscovitine, which inhibit the cell cycle at different points, block MCE, expression of cell cycle and adipocyte markers, as well as adipogenesis. These results show that MCE is a prerequisite for differentiation of 3T3-L1 preadipocytes into adipocytes.cell cycle ͉ adipogenesis ͉ 3T3-L1 preadipocyte ͉ C͞EBP␣ ͉ PPAR␥

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“…The expression of HSL is initiated at approximately the same time (17), leading to an increase in cytosolic lipase activity concomitant with increased expression of the proteins that facilitate glucose and fatty acid uptake, transport, and metabolism and the enzymes that catalyze triacylglycerol synthesis (17). Thus, the timing of the initiation of perilipin expression is critical to facilitate triacylglycerol storage in an increasingly lipolytic environment.…”

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confidence: 99%

The Amino and Carboxyl Termini of Perilipin A Facilitate the Storage of Triacylglycerols

Garcia

Subramanian

Sekowski

et al. 2004

Journal of Biological Chemistry

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Perilipin A is the most abundant lipid droplet-associated protein in adipocytes and serves important functions in regulating triacylglycerol levels by reducing rates of basal lipolysis and facilitating hormonally stimulated lipolysis. We have previously shown that the central region of perilipin A targets and anchors it to lipid droplets, at least in part via three moderately hydrophobic sequences that embed the protein into the hydrophobic core of the droplet. The current study examines the roles of the amino and carboxyl termini of perilipin A in facilitating triacylglycerol storage. Amino-and carboxyl-terminal truncation mutations of mouse perilipin A were stably expressed in 3T3-L1 preadipocytes, which lack perilipins. Triacylglycerol content of the cells was quantified as a measure of perilipin function and was compared with that of cells expressing full-length perilipin A or control cells lacking perilipins. The aminoterminal sequence between amino acids 122 and 222, including four 10 -11-amino acid sequences predicted to form amphipathic ␤-strands and a consensus site for cAMP-dependent protein kinase, and the carboxyl terminus of 112 amino acids that is unique to perilipin A were critical to facilitate triacylglycerol storage. The precocious expression of full-length perilipin A in 3T3-L1 preadipocytes aided more rapid storage of triacylglycerol during adipose differentiation. By contrast, the expression of highly truncated amino-or carboxylterminal mutations of perilipin failed to serve a dominant negative function in lowering triacylglycerol storage during adipose differentiation. We conclude that the amino and carboxyl termini are critical to the function of perilipin A in facilitating triacylglycerol storage.Triacylglycerols packaged within the lipid droplets of adipocytes provide the most abundant form of stored energy in the body. Lipid droplets are spherical structures composed of a core of neutral lipids coated by a phospholipid monolayer into which specific proteins are embedded. The study of lipid dropletassociated proteins is an emerging field of inquiry. Only a few of the component proteins have been identified, and little is known about the structural properties that define lipid dropletassociated proteins and facilitate their functions in lipid metabolism. The aim of the current study is to begin to define functional domains of perilipins, the first identified mammalian lipid droplet-associated proteins.Perilipins coating the surfaces of adipocyte lipid droplets serve as gatekeeper proteins controlling both the storage and release of triacylglycerol. The translation of alternatively spliced mRNAs produces three protein isoforms of perilipin: perilipins A, B, and C (1, 2). Perilipin A is the most abundant protein located at the surfaces of lipid droplets in adipocytes and is found at lower relative abundance on lipid droplets in steroidogenic cells of the adrenal cortex, testes, and ovaries (3); perilipin B is found at lower levels in both types of cells, and perilipin C is selectively expre...

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Regulation of Adipocyte Development

Cited by 594 publications

References 78 publications

EPAS1 Promotes Adipose Differentiation in 3T3-L1 Cells

EPAS1 Promotes Adipose Differentiation in 3T3-L1 Cells

Mitotic clonal expansion: A synchronous process required for adipogenesis

The Amino and Carboxyl Termini of Perilipin A Facilitate the Storage of Triacylglycerols

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