Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells.

Pekala, Phillip H.; Kawakami, Masanobu; Angus, Caroline; Lane, M. Daniel; Cerami, Anthony

doi:10.1073/pnas.80.9.2743

Cited by 125 publications

(71 citation statements)

References 18 publications

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“…20 TNF-a was shown to inhibit the synthesis of lipoprotein lipase (LPL), 63 acetyl-CoA-carboxylase (ACC) and fatty acid synthase (FAS). 64 In addition, TNF-a levels were found to be positively associated with UCP2 mRNA expression. 20 All these changes in enzyme activity and gene expression induced by the increased TNF-a in adipose tissue after feeding of CLA favor a decrease in fat cell size.…”

Section: Cla Increases Apoptosis Of Adipocytesmentioning

confidence: 98%

Conjugated linoleic acid and obesity control: efficacy and mechanisms

2004

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Obesity is associated with high blood cholesterol and high risk for developing diabetes and cardiovascular disease. Therefore, management of body weight and obesity are increasingly considered as an important approach to maintaining healthy cholesterol profiles and reducing cardiovascular risk. The present review addresses the effects of conjugated linoleic acid (CLA) on fat deposition, body weight and composition, safety, as well as mechanisms involved in animals and humans. Animal studies have shown promising effects of CLA on body weight and fat deposition. The majority of the animal studies have been conducted using CLA mixtures that contained approximately equal amounts of trans-10, cis-12 (t10c12) and cis-9, trans-11 (c9t11) isomers. Results of a few studies in mice fed CLA mixtures with different ratios of c9t11 and t10c12 isomers have indicated that the t10c12 isomer CLA may be the active form of CLA affecting weight gain and fat deposition. Inductions of leptin reduction and insulin resistance are the adverse effects of CLA observed in only mice. In pigs, the effects of CLA on weight gain and fat deposition are inconsistent, and no adverse effects of CLA have been reported. A number of human studies suggest that CLA supplementation has no effect on body weight and insulin sensitivity. Although it is suggested that the t10c12 CLA is the antiadipogenic isomer of CLA in humans, the effects of CLA on fat deposition are marginal and more equivocal as compared to results observed in animal studies. Mechanisms through which CLA reduces body weight and fat deposition remain to be fully understood. Proposed antiobesity mechanisms of CLA include decreased energy/food intake and increased energy expenditure, decreased preadipocyte differentiation and proliferation, decreased lipogenesis, and increased lipolysis and fat oxidation. In summary, CLA reduces weight gain and fat deposition in rodents, while produces less significant and inconsistent effects on body weight and composition in pigs and humans. New studies are required to examine isomer-specific effects and mechanisms of CLA in animals and humans using purified individual CLA isomers.

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Section: Cla Increases Apoptosis Of Adipocytesmentioning

confidence: 98%

Conjugated linoleic acid and obesity control: efficacy and mechanisms

2004

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“…In previous studies we have demonstrated that a macrophage mediator, secreted in response to endotoxin, switched adipose tissue in vivo (11) and 3T3-L1 adipocytes in vitro (3,4) from an anabolic storage mode to a catabolic state. By an unknown mechanism, this macrophage mediator can selectively inhibit the biosynthesis of several anabolic enzymes without adversely affecting the synthesis of most other proteins within the cell.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular explanation for this insulin resistance has remained obscure. Recently, we have observed that a form of insulin resistance occurs in 3T3-L 1 adipocytes in culture when these cells are incubated in the presence of a macrophage mediator that is m a d e in response to endotoxin (3,4). We believe that this m a c r o p h a g e mediator functions as a signal to the energy storage cells of the body for selective energy mobilization needed to combat host invasion.…”

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confidence: 99%

“…We believe that this m a c r o p h a g e mediator functions as a signal to the energy storage cells of the body for selective energy mobilization needed to combat host invasion. Biochemical analysis has revealed that this mediator can selectively inhibit the synthesis of several anabolic enzymes in these cells, including lipoprotein lipase, acetyl Co-A carboxylase, and fatty acid synthetase (3,4). Preliminary studies have demonstrated an inability of insulin, even at pharmacological concentrations, to override this effect of the mediator on the 3T3-L 1 cells (3).…”

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confidence: 99%

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Studies of insulin resistance in adipocytes induced by macrophage mediator.

Pekala¹,

Kawakami²,

Vine³

et al. 1983

The Journal of Experimental Medicine

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An apparent insulin resistance is noted in 3T3-L1 adipocytes after the addition of an endotoxin-induced mediator from macrophages. Examination at the level of the insulin receptor has revealed that the mediator does not effect either the functional ability of the cells to bind insulin or the ability of insulin to stimulate the uptake of glucose. The resistance appears to reflect a post-receptor interference with the insulin-induced biosynthesis of the anabolic enzymes, acetyl Co-A carboxylase and fatty acid synthetase, which are required for the conversion of glucose into storage lipid. These studies offer a new in vitro model for investigating the molecular basis of insulin resistance.

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“…In addition, rh cachectinlTNF had no effect on total RNA, poly(A)+ RNA, or actin mRNA concentration. It has previously been shown that TNF treatment of 3T3-L1 cultures causes no general effect on total protein synthesis (31,32), and polyacrylamide gel electrophoresis reveals that only a few proteins have visibly different amounts (32).…”

mentioning

confidence: 99%

Recombinant human cachectin/tumor necrosis factor but not interleukin-1 alpha downregulates lipoprotein lipase gene expression at the transcriptional level in mouse 3T3-L1 adipocytes.

Zechner¹,

Newman²,

Sherry³

et al. 1988

Mol. Cell. Biol.

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101

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Lipoprotein lipase (LPL) is synthesized primarily in muscle and adipose tissue and by hydrolyzing triglycerides in chylomicrons and very low density lipoprotein allows uptake of the resultant free fatty acids by these tissues. This report describes the cloning of the mouse LPL gene from which probes were derived to study the regulation of LPL synthesis in the 3T3-L1 adipocyte cell culture system. Preconfluent 3T3-L1 preadipocytes had very small amounts of LPL mRNA (<1 pg/,ug of RNA). At confluency, LPL mRNA levels increased to 5 to 15 pgl,Lg of RNA. After insulin and dexamethasone were added, LPL activity and mRNA levels rose in parallel. Peak mRNA levels were reached within 4 to 10 days, achieving LPL mRNA concentrations of 150 to 500 pg/,ug of RNA. This represents a 15-to 50-fold increase over confluent cells. Two cytokines known to diminish adipose tissue LPL activity were studied to see how their effects were regulated. Recombinant human cachectin/tumor necrosis factor diminished both LPL activity and LPL mRNA levels. The effect on LPL activity compared with mRNA levels was quicker, at a lower dose, and more complete (95 versus 75% maximum effect). The effect of recombinant human cachectin tumor necrosis factor on LPL mRNA levels was shown by nuclear run-on experiments to be exerted transcriptionally. It was also independent of new protein synthesis. Recombinant human interleukin-la diminished only LPL activity but not mRNA levels. This study suggests that during times of stress, cytokines secreted by activated macrophages can alter energy balance by affecting transcriptional and posttranscriptional processes in adipocytes.

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Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells.

Cited by 125 publications

References 18 publications

Conjugated linoleic acid and obesity control: efficacy and mechanisms

Conjugated linoleic acid and obesity control: efficacy and mechanisms

Studies of insulin resistance in adipocytes induced by macrophage mediator.

Recombinant human cachectin/tumor necrosis factor but not interleukin-1 alpha downregulates lipoprotein lipase gene expression at the transcriptional level in mouse 3T3-L1 adipocytes.

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