Selectivity of fatty acids on lipid metabolism and gene expression

Raclot, Thierry; Oudart, Hugues

doi:10.1017/s002966519900083x

Cited by 55 publications

(46 citation statements)

References 116 publications

(105 reference statements)

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“…Evidence for substrate specificity of HSL in vitro has been reported recently (49). The substrate specificity of HSL might be associated with the polarity of TG in adipose tissue (19,50,51).…”

Section: Discussionmentioning

confidence: 90%

“…These effects are explained by the ability of FFA and their derivatives to regulate lipogenic genes by the activation of nuclear receptors including peroxisome proliferator-activated receptors and sterol-responsive element-binding protein-1/adipocyte differentiation-dependent factor (17)(18)(19)(20)(21). Thus, HSL is considered to be an important enzyme in the maintenance of energy homeostasis.…”

Section: Hormone-sensitive Lipase (Hsl)mentioning

confidence: 99%

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Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Haemmerle¹,

Zimmermann²,

Hayn³

et al. 2002

Journal of Biological Chemistry

543

532

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Hormone-sensitive lipase (HSL) is expressed predominantly in white and brown adipose tissue where it is believed to play a crucial role in the lipolysis of stored triglycerides (TG), thereby providing the body with energy substrate in the form of free fatty acids (FFA). From in vitro assays, HSL is known to hydrolyze TG, diglycerides (DG), cholesteryl esters, and retinyl esters. In the current study we have generated HSL knock-out mice and demonstrate three lines of evidence that HSL is instrumental in the catabolism of DG in vivo. First, HSL deficiency in mice causes the accumulation of DG in white adipose tissue, brown adipose tissue, skeletal muscle, cardiac muscle, and testis. Second, when tissue extracts were used in an in vitro lipase assay, a reduced FFA release and the accumulation of DG was observed in HSL knock-out mice which did not occur when tissue extracts from control mice were used. Third, in vitro lipolysis experiments with HSL-deficient fat pads demonstrated that the isoproterenol-stimulated release of FFA was decreased and DG accumulated intracellularly resulting in the essential absence of the isoproterenolstimulated glycerol formation typically observed in control fat pads. Additionally, the absence of HSL in white adipose tissue caused a shift of the fatty acid composition of the TG moiety toward increased long chain fatty acids implying a substrate specificity of the enzyme in vivo. From these in vivo results we conclude that HSL is the rate-limiting enzyme for the cellular catabolism of DG in adipose tissue and muscle. Hormone-sensitive lipase (HSL)1 is thought to be a key enzyme for the mobilization of triglycerides (TG) deposited in adipose tissue. Human HSL is composed of 775 amino acids that are encoded by a 2.9-kb mRNA transcribed from a single gene composed of 9 exons (1, 2). The mouse and the human genes are similar in size and share a high degree of sequence homology. A tissue-specific size variation has been observed in testis where an additional exon 13 kb upstream of exon 1 in adipose tissue gives rise to a 3.9-kb mRNA and a 1076-amino acid protein (3). The molecular basis of size variations in HSL mRNA in muscle, macrophages, and ovaries is unknown.HSL-mediated lipolysis is strictly controlled by hormones. The enzyme is activated by catecholamines and other lipolytic hormones upon phosphorylation by the cAMP-dependent protein kinase A and the lipotransin-mediated translocation of the enzyme from the cytoplasm to the lipid droplet (4 -6). Insulin, the major antilipolytic hormone, inhibits HSL through phosphodiesterase-3-dependent cAMP degradation and interference with the lipotransin-mediated enzyme translocation. Accordingly, mice with elevated protein kinase A activity exhibit increased lipolysis and a lean phenotype (7). Absence of perilipin in mice also resulted in leanness through constitutive activation of HSL (8). Conversely, mice that lack the insulin receptor substrate 2 become obese (9). These results imply that imbalances between lipid accumulation and fat mobilizati...

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Section: Discussionmentioning

confidence: 90%

Section: Hormone-sensitive Lipase (Hsl)mentioning

confidence: 99%

Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Haemmerle¹,

Zimmermann²,

Hayn³

et al. 2002

Journal of Biological Chemistry

543

532

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“…Therefore, we cannot exclude the possibility that insulin resistance may have had an effect on desaturase activities. Other factors that may be involved are changes in insulin [40] or glucose itself, changes in leptin concentration [41] or changes in fatty acid handling with different preferences for saturated or unsaturated fatty acids in lipolytic and oxidative processes [42,43]. One challenge for future studies is to elucidate whether and how lifestyle factors can modify desaturase enzyme activities with consequences for the insulin-resistant state, and whether and how changes in metabolic profile, e.g.…”

Section: Discussionmentioning

confidence: 99%

Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study

et al. 2006

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Aims/hypothesis The aim of this study was to investigate whether lifestyle intervention-induced changes in serum fatty acid profile of cholesteryl esters and estimated desaturase activities are related to improvements in insulin sensitivity in subjects at risk of type 2 diabetes. Materials and methods In the Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM), 97 men and women with IGT were randomised to a combined diet and exercise programme (47 intervention) or a control group (50 control subjects). At baseline and after 1 year the following assessments were made: an OGTT, an exercise test to determine maximal aerobic capacity, anthropometry, and analysis of the serum fatty acid profile of cholesteryl esters. Results The lifestyle programme was effective in reducing the intake of total and saturated fat, increasing physical activity, reducing obesity and improving insulin sensitivity and glucose tolerance. Regression analysis of the total population showed that an increase in the C20:4 n-6/C20:3 n-6 ratio (estimated Δ5-desaturase activity) and reductions in the C18:3 n-6/C18:2 n-6 ratio (estimated Δ6-desaturase activity) and the C16:1 n-7/C16:0 ratio (estimated Δ9-desaturase activity or stearoyl-CoA desaturase-1) were significantly associated with a decrease in homeostasis model assessment for insulin resistance. After adjustment for lifestyle changes (change in percentage body fat, aerobic capacity and saturated fat intake), these associations were partly reduced, but remained statistically significant. Conclusions/interpretation Lifestyle-induced changes in fatty acid profile of cholesteryl esters and desaturase activities were independently related to changes in insulin sensitivity in subjects at risk of type 2 diabetes.

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“…In humans, whole-body lipid oxidation was increased by dietary fish oil [11]. The anti-adipogenic effect of n-3 PUFA may be also mediated by changes occurring in white adipose tissue itself [5,15]. Studies in rodents indicate a complex modulation of gene expression in white adipose tissue by n-3 PUFA [6,12], especially in fat depots in the abdominal region, which are preferentially reduced [3,5,6,8,16].…”

Section: Introductionmentioning

confidence: 99%

Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat

et al. 2005

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Aims/hypothesis: Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor α-linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. Methods: The effects of EPA/ DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. Results: Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in α-linolenic acid. This was associated with a threefold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1α] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite highfat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. Conclusions/interpretation: The antiadipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of β-oxidation and upregulation of mitochondrial biogenesis.

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Selectivity of fatty acids on lipid metabolism and gene expression

Cited by 55 publications

References 116 publications

Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study

Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat

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