Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role for Elovl3 during increased fatty acid oxidation

2005 ◽  
Vol 289 (4) ◽  
pp. E517-E526 ◽  
Author(s):  
Andreas Jakobsson ◽  
Johanna A. Jörgensen ◽  
Anders Jacobsson
Keyword(s):  
Fatty Acid ◽  
Gene Family ◽  
Regulatory Element ◽  
Saturated Fatty Acids ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Brown Adipose

The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor-α (PPARα) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPARα ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

scholarly journals Ergosterol Peroxide from the Medicinal Mushroom Ganoderma lucidum Inhibits Differentiation and Lipid Accumulation of 3T3-L1 Adipocytes

2020 ◽  
Vol 21 (2) ◽  
pp. 460 ◽  
Author(s):  
Yong-Un Jeong ◽  
Young-Jin Park
Keyword(s):  
Transcription Factors ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
Binding Protein ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Medicinal Mushrooms ◽  
Ergosterol Peroxide

Ergosterol peroxide is a natural compound of the steroid family found in many fungi, and it possesses antioxidant, anti-inflammatory, anticancer and antiviral activities. The anti-obesity activity of several edible and medicinal mushrooms has been reported, but the effect of mushroom-derived ergosterol peroxide on obesity has not been studied. Therefore, we analyzed the effect of ergosterol peroxide on the inhibition of triglyceride synthesis at protein and mRNA levels and differentiation of 3T3-L1 adipocytes. Ergosterol peroxide inhibited lipid droplet synthesis of differentiated 3T3-L1 cells, expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAT/enhancer-binding protein alpha (C/EBPα), the major transcription factors of differentiation, and also the expression of sterol regulatory element-binding protein-1c (SREBP-1c), which promotes the activity of PPARγ, resulting in inhibition of differentiation. It further inhibited the expression of fatty acid synthase (FAS), fatty acid translocase (FAT), and acetyl-coenzyme A carboxylase (ACC), which are lipogenic factors. In addition, it inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) involved in cell proliferation and activation of early differentiation transcription factors in the mitotic clonal expansion (MCE) stage. As a result, ergosterol peroxide significantly inhibited the synthesis of triglycerides and differentiation of 3T3-L1 cells, and is, therefore, a possibile prophylactic and therapeutic agent for obesity and related metabolic diseases.

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

2008 ◽  
Vol 295 (2) ◽  
pp. E287-E296 ◽  
Author(s):  
Natasa Petrovic ◽  
Irina G. Shabalina ◽  
James A. Timmons ◽  
Barbara Cannon ◽  
Jan Nedergaard
Keyword(s):  
Primary Cultures ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Sympathetic Stimulation ◽  
Promoting Effect ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Brown Adipose

Most physiologically induced examples of recruitment of brown adipose tissue (BAT) occur as a consequence of chronic sympathetic stimulation (norepinephrine release within the tissue). However, in some physiological contexts (e.g., prenatal and prehibernation recruitment), this pathway is functionally contraindicated. Thus a nonsympathetically mediated mechanism of BAT recruitment must exist. Here we have tested whether a PPARγ activation pathway could competently recruit BAT, independently of sympathetic stimulation. We continuously treated primary cultures of mouse brown (pre)adipocytes with the potent peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone. In rosiglitazone-treated cultures, morphological signs of adipose differentiation and expression levels of the general adipogenic marker aP2 were manifested much earlier than in control cultures. Importantly, in the presence of the PPARγ agonist the brown adipocyte phenotype was significantly enhanced: UCP1 was expressed even in the absence of norepinephrine, and PPARα expression and norepinephrine-induced PGC-1α mRNA levels were significantly increased. However, the augmented levels of PPARα could not explain the brown-fat promoting effect of rosiglitazone, as this effect was still evident in PPARα-null cells. In continuously rosiglitazone-treated brown adipocytes, mitochondriogenesis, an essential part of BAT recruitment, was significantly enhanced. Most importantly, these mitochondria were capable of thermogenesis, as rosiglitazone-treated brown adipocytes responded to the addition of norepinephrine with a large increase in oxygen consumption. This thermogenic response was not observable in rosiglitazone-treated brown adipocytes originating from UCP1-ablated mice; hence, it was UCP1 dependent. Thus the PPARγ pathway represents an alternative, potent, and fully competent mechanism for BAT recruitment, which may be the cellular explanation for the enigmatic recruitment in prehibernation and prenatal states.

scholarly journals Modulation of Fatty Acid-Related Genes in the Response of H9c2 Cardiac Cells to Palmitate and n-3 Polyunsaturated Fatty Acids

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 537
Author(s):  
Silvia Cetrullo ◽  
Stefania D’Adamo ◽  
Veronica Panichi ◽  
Rosa Maria Borzì ◽  
Carla Pignatti ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Polyunsaturated Fatty Acids ◽  
Molecular Mechanisms ◽  
Dietary Habits ◽  
Regulatory Element ◽  
Saturated Fatty Acids ◽  
Cardiac Cells ◽  
High Dose ◽  
Mrna Levels

While high levels of saturated fatty acids are associated with impairment of cardiovascular functions, n-3 polyunsaturated fatty acids (PUFAs) have been shown to exert protective effects. However the molecular mechanisms underlying this evidence are not completely understood. In the present study we have used rat H9c2 ventricular cardiomyoblasts as a cellular model of lipotoxicity to highlight the effects of palmitate, a saturated fatty acid, on genetic and epigenetic modulation of fatty acid metabolism and fate, and the ability of PUFAs, eicosapentaenoic acid, and docosahexaenoic acid, to contrast the actions that may contribute to cardiac dysfunction and remodeling. Treatment with a high dose of palmitate provoked mitochondrial depolarization, apoptosis, and hypertrophy of cardiomyoblasts. Palmitate also enhanced the mRNA levels of sterol regulatory element-binding proteins (SREBPs), a family of master transcription factors for lipogenesis, and it favored the expression of genes encoding key enzymes that metabolically activate palmitate and commit it to biosynthetic pathways. Moreover, miR-33a, a highly conserved microRNA embedded in an intronic sequence of the SREBP2 gene, was co-expressed with the SREBP2 messenger, while its target carnitine palmitoyltransferase-1b was down-regulated. Manipulation of the levels of miR-33a and SREBPs allowed us to understand their involvement in cell death and hypertrophy. The simultaneous addition of PUFAs prevented the effects of palmitate and protected H9c2 cells. These results may have implications for the control of cardiac metabolism and dysfunction, particularly in relation to dietary habits and the quality of fatty acid intake.

scholarly journals A role for PPARα in the control of SREBP activity and lipid synthesis in the liver

2005 ◽  
Vol 389 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Brian L. Knight ◽  
Abdel Hebbachi ◽  
David Hauton ◽  
Anna-Marie Brown ◽  
David Wiggins ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cholesterol Synthesis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
Active Form ◽  
Dietary Cholesterol ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Hepatic Expression

Inclusion of the PPARα (peroxisome-proliferator-activated receptor α) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARα expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARα-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.

scholarly journals Peroxisomal-proliferator-activated receptor alpha activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level

2004 ◽  
Vol 378 (3) ◽  
pp. 983-990 ◽  
Author(s):  
Gha Young LEE ◽  
Nam Hee KIM ◽  
Zheng-Shan ZHAO ◽  
Bong Soo CHA ◽  
Y. Sam KIM
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Retinoid X Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Malonyl Coa ◽  
Promoter Deletion Analysis

MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARα (peroxisome-proliferator-activated receptor α) (−/−) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098–4103]. This suggests that MCD may be transcriptionally regulated by PPARα. To investigate whether PPARα is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARα/retinoid X receptor α expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARα/retinoid X receptor α heterodimer indeed bound to the two PPREs, and the binding specificity of PPARα on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARα activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARα can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARα and fatty-acid oxidation by altering the malonyl-CoA concentration.

scholarly journals Anti-Adipogenic Effect of Neferine in 3T3-L1 Cells and Primary White Adipocytes

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1858
Author(s):  
Miey Park ◽  
Jinyoung Han ◽  
Hae-Jeung Lee
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Antioxidant Properties ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Dependent Manner

Neferine, an alkaloid component extracted from lotus seed embryos, is known for its anti-inflammatory, anticancer, and antioxidant properties. However, the anti-adipogenic activity of neferine has not been thoroughly investigated. In this study, neferine was found to inhibit lipid accumulation in a dose-dependent manner during the differentiation of 3T3-L1 cells without inducing cytotoxicity. Real-time polymerase chain reaction and immunoblot analysis revealed the downregulation in the expression of peroxisome proliferator activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS) and the upregulation in carnitine palmitoyltransferase-1 (CPT-1) and sirtuin 1 (SIRT1) levels following neferine treatment. Furthermore, neferine increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which is an important regulator of fatty acid oxidation. Our result indicates that neferine attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling. Therefore, neferine may serve as a therapeutic candidate for obesity treatment.

scholarly journals Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma.

1996 ◽  
Vol 16 (7) ◽  
pp. 3410-3419 ◽  
Author(s):  
I B Sears ◽  
M A MacGinnitie ◽  
L G Kovacs ◽  
R A Graves
Keyword(s):  
Protein Binding ◽  
Uncoupling Protein ◽  
Ppar Gamma ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

Uncoupling protein (UCP) is expressed only in brown adipocytes and is responsible for the unique thermogenic properties of this cell type. The novel brown preadipocyte cell line, HIB-1B, expresses UCP in a strictly differentiation-dependent manner. Transgenic mice studies have shown that a region from kb -2.8 to -1.0 of the marine UCP gene is required for brown adipocyte-specific expression. Subsequent analysis identified a potent 220-bp enhancer from kb -2.5 to -2.3. We show that this enhancer is active only in differentiated HIB-1B adipocytes, and we identify a peroxisome proliferator-activated receptor gamma (PPARgamma) response element, referred to as UCP regulatory element 1 (URE1), within the enhancer. URE1 has differentiation-dependent enhancing activity in HIB-1B cells and is required for enhancer action, since mutations of URE1 that block protein binding abolish enhancer activity. We also show that PPAR gamma antibodies block binding to URE1 of nuclear extracts from cultured brown adipocytes and from the brown adipose tissue of cold-exposed mice. Protein binding to URE1 increases substantially during differentiation of HIB-1B preadipocytes, and PPAR-gamma mRNA levels increase correspondingly. Although forced expression of PPAR gamma and retinoid X receptor alpha activates the enhancer in HIB-1B preadipocytes, these receptors are not capable of activating the enhancer in NIH 3T3 fibroblasts. Our results show that PPAR gamma is a regulator of the differentiation-dependent expression of UCP and suggest that there are additional factors in HIB-1B cells required for brown adipocyte-specific UCP expression.

scholarly journals Cold-induction of afadin in brown fat supports its thermogenic capacity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morten Lundh ◽  
Ali Altıntaş ◽  
Marco Tozzi ◽  
Odile Fabre ◽  
Tao Ma ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Functional Enrichment ◽  
Activation Process ◽  
Target Tissue ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Protein Levels ◽  
Mrna Induction ◽  
Metabolic Functions ◽  
Brown Adipose

AbstractThe profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

scholarly journals Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue

iScience ◽  
2021 ◽  
pp. 102434
Author(s):  
Winifred W. Yau ◽  
Kiraely Adam Wong ◽  
Jin Zhou ◽  
Nivetha Kanakaram Thimmukonda ◽  
Yajun Wu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Fatty Acid Oxidation ◽  
Cold Exposure ◽  
Acid Oxidation ◽  
Brown Adipose ◽  
Mitochondrial Turnover
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