Inhibition of fatty acid synthase prevents preadipocyte differentiation

Schmid, Bernhard; Rippmann, Jörg F.; Tadayyon, Moh; Hamilton, Bradford S.

doi:10.1016/j.bbrc.2005.01.067

Cited by 127 publications

(91 citation statements)

References 32 publications

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“…2). As expected, the well established required factors for adipocyte differentiation, PPAR␥ and FAS (21), did indeed attenuate PPAR␥ and GLUT4 expression in this screen when depleted by siRNA and acted as positive controls. In addition, rosiglitazone treatment did not restore PPAR␥ or GLUT4 levels upon siRNA-based depletion of PPAR␥ ( Fig.…”

Section: Expression Of Fatty Acid Metabolizing Enzymes In Culturedsupporting

confidence: 81%

“…Furthermore, overexpression of sterol regulatory element-binding protein-1 (SREBP1) in adipocytes apparently increases ligand production (19), whereas inhibition of acetyl-CoA carboxylase (ACC) (20) or fatty acid synthase (FAS) (21) inhibits adipogenesis. SREBP1 is a transcription factor that controls the expression of many fatty acid metabolizing enzymes, including ACC and FAS.…”

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confidence: 99%

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Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor γ Expression and Adipogenesis in Cultured 3T3-L1 Cells

Christianson

Nicoloro

Straubhaar

et al. 2008

Journal of Biological Chemistry

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Based on recent evidence that fatty acid synthase and endogenously produced fatty acid derivatives are required for adipogenesis in 3T3-L1 adipocytes, we conducted a small interfering RNA-based screen to identify other fatty acid-metabolizing enzymes that may mediate this effect. Of 24 enzymes screened, stearoyl-CoA desaturase 2 (SCD2) was found to be uniquely and absolutely required for adipogenesis. Remarkably, SCD2 also controls the maintenance of adipocyte-specific gene expression in fully differentiated 3T3-L1 adipocytes, including the expression of SCD1. Despite the high sequence similarity between SCD2 and SCD1, silencing of SCD1 did not down-regulate 3T3-L1 cell differentiation or gene expression. SCD2 mRNA expression was also uniquely elevated 44-fold in adipose tissue upon feeding mice a high fat diet, whereas SCD1 showed little response. The inhibition of adipogenesis caused by SCD2 depletion was associated with a decrease in peroxisome proliferatoractivated receptor ␥ (PPAR␥) mRNA and protein, whereas in mature adipocytes loss of SCD2 diminished PPAR␥ protein levels, with little change in mRNA levels. In the latter case, SCD2 depletion did not change the degradation rate of PPAR␥ protein but decreased the metabolic labeling of PPAR␥ protein using [ 35 S]methionine/cysteine, indicating protein translation was decreased. This requirement of SCD2 for optimal protein synthesis in fully differentiated adipocytes was verified by polysome profile analysis, where a shift in the mRNA to monosomes was apparent in response to SCD2 silencing. These results reveal that SCD2 is required for the induction and maintenance of PPAR␥ protein levels and adipogenesis in 3T3-L1 cells.The ability of adipocytes to sense and respond to circulating fatty acid levels is important in maintaining the proper balance between fatty acid storage and fatty acid release for energy utilization. In the case of energy excess, fatty acids are stored in the form of triglyceride, and new adipocytes are generated to efficiently metabolize amino acids, glucose, and fatty acids to triglyceride (1). The key regulator of adipogenesis, the process whereby preadipocytes differentiate into fully mature adipocytes, is the ligand-activated nuclear receptor PPAR␥ 2 (2). Cultured mouse 3T3-L1 preadipocytes are an excellent model system for the study of adipogenesis. These cells differentiate into adipocytes with multilocular lipid droplets through a transcriptional cascade beginning with the rapid and transient expression of C/EBP␤ and C/EBP␦ (3, 4). The up-regulation of these transcription factors precedes the expression of PPAR␥ and C/EBP␣, which are critical for the completion of adipogenesis as well as the maintenance of adipocyte-specific gene expression in fully differentiated cells (3, 4). Other transcription factors have also been shown to play significant roles in adipogenesis and adipocyte biology (for reviews, see Refs. 3, 5, and 6). However, because PPAR␥ controls the expression of large sets of genes required to maintain the adipocyte phen...

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Section: Expression Of Fatty Acid Metabolizing Enzymes In Culturedsupporting

confidence: 81%

mentioning

confidence: 99%

Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor γ Expression and Adipogenesis in Cultured 3T3-L1 Cells

Christianson

Nicoloro

Straubhaar

et al. 2008

Journal of Biological Chemistry

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“…Previously, it has been shown that inhibition of FASN activity suppresses the expression of peroxisome proliferatoractivated receptor γ (PPARγ) in mice 3T3 cells (Schmid et al, 2005). Decreased PPARγ suppresses the expression of ACCα in human THP-1 cells (Chawla et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of FASN reduces the synthesis of medium-chain fatty acids in goat mammary gland

Zhu

Luo

Wang

et al. 2014

Animal

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Fatty acid synthase (FASN) is known as a crucial enzyme of cellular de novo fatty acid synthesis in mammary gland which has been proved as the main source of short and medium-chain fatty acids of milk. However, the regulatory role of FASN in goat-specific milk fatty acids composition remains unclear. We cloned and analyzed the full-length of FASN gene from the mammary gland of Capra hircus (Xinong Saanen dairy goat) (DQ 915966). Comparative gene expression analysis suggested that FASN is predominantly expressed in fat, small intestine and mammary gland tissues, and expresses higher level at lactation period. Inhibition of FASN activity by different concentrations (0, 5, 15, 25 and 35 μM) of orlistat, a natural inhibitor of FASN, resulted in decreased expression of acetyl-CoA carboxylase α (ACCα), lipoprotein lipase and heart-type fatty acid binding protein (H-FABP) in a concentration-dependent manner in goat mammary gland epithelial cells (GMEC). Similar results were also obtained by silencing of FASN. Additionally, reduction of FASN expression also led to apparent decline of the relative content of decanoic acid (C10:0) and lauric acid (C12:0) in GMEC. Our study provides a direct evidence for inhibition of FASN reduces cellular medium-chain fatty acids synthesis in GMEC.

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“…Triclosan is a potent inhibitor of the enoyl-acyl carrier protein reductase enzyme of the prokaryotic type II fatty acid synthase complex. Triclosan has also been reported to inhibit Type I fatty acid synthase in mammalian cells [29,30]. At concentrations shown not to be cytotoxic in preadipocytes (50 μM) [34] triclosan was a strong inhibitor of insulin release from islet cells (Figure 4) and INS-1 832/13 cells ( Figure 5).…”

Section: Inhibition Of Insulin Release By Inhibitors Of Lipogenesismentioning

confidence: 92%

“…Triclosan (5-chloro-2-(2,4-dichlorophenoxy)-phenol) was from Fluka BioChemika. Anti-actin (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) antibody (catalog number A5060) and other chemicals were from Sigma. INS-1 832/13 cells were from Chris Newgard [22].…”

Section: Experimental Procedures Materialsmentioning

confidence: 99%

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

MacDonald

Dobrzyń

Ntambi

et al. 2008

Archives of Biochemistry and Biophysics

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Pancreatic beta cell mitochondria convert insulin secretagogues into products that support insulin exocytosis. We explored the idea that lipids are some of these products formed from acyl group transfer out of mitochondria to the cytosol, the site of lipid synthesis. There are two isoforms of acetyl-CoA carboxylase, the enzyme that forms malonyl-CoA from which C 2 units for lipid synthesis are formed. We found that ACC1, the isoform seen in lipogenic tissues, is the only isoform present in human and rat pancreatic islets and INS-1 832/13 cells. Inhibitors of ACC and fatty acid synthase inhibited insulin release in islets and INS-1 cells. Carbon from glucose and pyruvate were rapidly incorporated into many lipid classes in INS-1 cells. Glucose and other insulin secretagogues acutely increased many lipids with C 14 -C 24 chains including individual cholesterol esters, phospholipids and fatty acids. Many phosphatidylcholines and phosphatidylserines were increased and many phosphatidylinositols and several phosphatidylethanolamines were decreased. The results suggest that lipid remodeling and rapid lipogenesis from secretagogue carbon support insulin secretion.

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Inhibition of fatty acid synthase prevents preadipocyte differentiation

Cited by 127 publications

References 32 publications

Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor γ Expression and Adipogenesis in Cultured 3T3-L1 Cells

Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor γ Expression and Adipogenesis in Cultured 3T3-L1 Cells

Inhibition of FASN reduces the synthesis of medium-chain fatty acids in goat mammary gland

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

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