scholarly journals Peroxisome Proliferator-Activated Receptor-α Control of Lipid and Glucose Metabolism in Human White Adipocytes

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 123-133 ◽  
Author(s):  
Carole Ribet ◽  
Emilie Montastier ◽  
Carine Valle ◽  
Véronic Bezaire ◽  
Anne Mazzucotelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Biological Effects ◽  
Primary Cultures ◽  
Lactate Production ◽  
De Novo Lipogenesis ◽  
Peroxisome Proliferator ◽  
Palmitate Oxidation ◽  
White Adipocytes ◽  
Pparγ Agonist ◽  
Pparα Agonist

Abstract This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)α in human white adipocyte metabolism and at comparing PPARα and PPARγ actions in these cells. Primary cultures of human fat cells were treated with the PPARα agonist GW7647 or the PPARγ agonist rosiglitazone. Changes in gene expression were determined using DNA microrrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of β-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPARα agonist. GW7647-induced alterations were abolished by a treatment with a PPARα antagonist. Small interfering RNA-mediated extinction of PPARα gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and β-oxidation. Altogether these results show that PPARα can selectively up-regulate β-oxidation and decrease glucose utilization in human white adipocytes.

scholarly journals A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle

2001 ◽  
Vol 280 (2) ◽  
pp. E270-E279 ◽  
Author(s):  
Anne Minnich ◽  
Nian Tian ◽  
Lisa Byan ◽  
Glenda Bilder
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Biological Effects ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Mitochondrial Fatty Acid ◽  
Cpt I ◽  
Pparα Agonist

The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-α (PPARα). Here we show that a PPARα agonist, ureido-fibrate-5 (UF-5), ∼200-fold more potent than fenofibric acid, exerts TG-lowering effects (37%) in fat-fed hamsters after 3 days at 30 mg/kg. In addition to lowering hepatic apolipoprotein C-III (apoC-III) gene expression by ∼60%, UF-5 induces hepatic mitochondrial carnitine palmitoyltransferase I (CPT I) expression. A 3-wk rising-dose treatment results in a greater TG-lowering effect (70%) at 15 mg/kg and a 2.3-fold elevation of muscle CPT I mRNA levels, as well as effects on hepatic gene expression. UF-5 also stimulated mitochondrial [3H]palmitate β-oxidation in vitro in human hepatic and skeletal muscle cells 2.7- and 1.6-fold, respectively, in a dose-related manner. These results suggest that, in addition to previously described effects of fibrates on apoC-III expression and on peroxisomal fatty acid (FA) β-oxidation, PPARα agonists stimulate mitochondrial FA β-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARα agonists.

scholarly journals PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

2021 ◽  
Vol 22 (19) ◽  
pp. 10431
Author(s):  
Gábor Kökény ◽  
Laurent Calvier ◽  
Georg Hansmann
Keyword(s):  
Transforming Growth Factor Beta ◽  
Kidney Failure ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Critical Conditions ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.

scholarly journals Diet-dependent Natriuretic Peptide Receptor C expression in adipose tissue is mediated by PPARγ via long-range distal enhancers

2021 ◽  
Author(s):  
Fubiao Shi ◽  
Zoltan Simandi ◽  
Laszlo Nagy ◽  
Sheila Collins
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Long Range ◽  
Environmental Changes ◽  
Peroxisome Proliferator ◽  
Enhancer Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Mouse Adipocytes ◽  
Sirna Knockdown

AbstractIn addition to their established role to maintain blood pressure and fluid volume, the cardiac natriuretic peptides (NPs) can stimulate adipocyte lipolysis and control the brown fat gene program of nonshivering thermogenesis. The NP “clearance” receptor C (NPRC) functions to clear NPs from the circulation via peptide internalization and degradation and thus is an important regulator of NP signaling and adipocyte metabolism. It is well appreciated that the Nprc gene is highly expressed in adipose tissue and is dynamically regulated with nutrition and environmental changes. However, the molecular basis for how Nprc gene expression is regulated is still poorly understood. Here we identified Peroxisome Proliferator-Activated Receptor gamma (PPARγ) as a transcriptional regulator of Nprc expression in mouse adipocytes. During 3T3-L1 adipocyte differentiation, levels of Nprc expression increase in parallel with PPARγ induction. Rosiglitazone, a classic PPARγ agonist, increases, while siRNA knockdown of PPARγ reduces, Nprc expression in 3T3-L1 adipocytes. We demonstrate that PPARγ controls Nprc gene expression in adipocytes through its long-range distal enhancers. Furthermore, the induction of Nprc expression in adipose tissue during high-fat diet feeding is associated with increased PPARγ enhancer activity. Our findings define PPARγ as a mediator of adipocyte Nprc gene expression and establish a new connection between PPARγ and the control of adipocyte NP signaling in obesity.

scholarly journals Peroxisome Proliferator-Activated Receptors-α and -γ, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1162-1173 ◽  
Author(s):  
Meritxell Rosell ◽  
Elayne Hondares ◽  
Sadahiko Iwamoto ◽  
Frank J. Gonzalez ◽  
Martin Wabitsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Retinol Binding Protein ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Retinol Binding Protein 4 ◽  
White Adipocytes ◽  
Brown Adipose ◽  
Rbp4 Gene

Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARγ and PPARα induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARα-null brown adipocytes or in the presence of inhibitors of PPARγ and PPARα. PPARγ and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARα confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARα, and PPARγ. This is mediated by a PPAR-responsive element capable of binding PPARα and PPARγ and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARγ-coactivator-1-α, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARγ- and PPARα-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARγ-coactivator-1-α coactivation of PPAR signaling.

NGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines

2004 ◽  
Vol 287 (2) ◽  
pp. E331-E339 ◽  
Author(s):  
Muhammad R. Peeraully ◽  
John R. Jenkins ◽  
Paul Trayhurn
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Sympathetic Neurons ◽  
Mrna Levels ◽  
Rt Pcr ◽  
White Adipocytes ◽  
Pparγ Agonist ◽  
Tnf Α ◽  
Ngf Gene

The sympathetic nervous system plays a central role in lipolysis and the production of leptin in white adipose tissue (WAT). In this study, we have examined whether nerve growth factor (NGF), a target-derived neurotropin that is a key signal in the development and survival of sympathetic neurons, is expressed and secreted by white adipocytes. NGF mRNA was detected by RT-PCR in the major WAT depots of mice (epididymal, perirenal, omental, mesenteric, subcutaneous) and in human fat (subcutaneous, omental). In mouse WAT, NGF expression was observed in mature adipocytes and in stromal vascular cells. NGF expression was also evident in 3T3-L1 cells before and after differentiation into adipocytes. NGF protein, measured by ELISA, was secreted from 3T3-L1 cells, release being higher before differentiation. Addition of the sympathetic agonists norepinephrine, isoprenaline, or BRL-37344 (β3-agonist) led to falls in NGF gene expression and secretion by 3T3-L1 adipocytes, as did IL-6 and the PPARγ agonist rosiglitazone. A substantial decrease in NGF expression and secretion occurred with dexamethasone. In contrast, LPS increased NGF mRNA levels and NGF secretion. A major increase in NGF mRNA level (9-fold) and NGF secretion (≤40-fold) in 3T3-L1 adipocytes occurred with TNF-α. RT-PCR showed that the genes encoding the p75 and trkA NGF receptors were expressed in mouse WAT. These results demonstrate that white adipocytes secrete NGF (an adipokine), NGF synthesis being influenced by several factors with TNF-α having a major stimulatory effect. We suggest that NGF is a target-derived neurotropin and an inflammatory response protein in white adipocytes.

155 Low Insulin Sensitivity Is Associated with Increased Body Fat and Changes in Gene Expression of Lipogenic Enzymes in the Adipose Tissue of Finishing Pigs

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 83-84
Author(s):  
Hector H Salgado ◽  
Marie-France Palin ◽  
Hélène Lapierre ◽  
Aline Remus ◽  
Marie-Pierre Letourneau-Montminy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
De Novo ◽  
Mrna Abundance ◽  
De Novo Lipogenesis ◽  
Peroxisome Proliferator ◽  
Lipogenic Enzymes ◽  
Glucose Ingestion

Abstract Variations in body fat (BF) among pigs can be associated with differences in insulin sensitivity given the insulin anabolic effect in lipid synthesis. The study objectives were to characterize this association and compare the relative mRNA abundance of genes associated with insulin resistance and de novo lipogenesis in the adipose tissue of fat and lean pigs. Thirty 95 kg pigs, catheterized in the jugular vein, received an oral dose of 1.75 g glucose/kg of BW after 18 hours of fasting. Blood samples were collected at -20, -10, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300 and 360 minutes following glucose ingestion. Insulin sensitivity indexes were calculated and analyzed. The BF (%) was estimated by dual X-ray densitometry. The 8 fattest (22 % BF) and the 8 leanest pigs (17.2 % BF) were used to determine the relative mRNA abundance of studied genes using real-time qPCR analyses. Insulin sensitivity was determined using QUICKI and Matsuda indexes, respectively, and their association with body fat was studied with Spearman correlations. Differences in gene expression and insulin sensitivity between fat and lean pigs were studied with a one-way ANOVA. The QUICKI and Matsuda indexes negatively correlated with BF (r = -0.67 and r = -0.59; P < 0.001). Fat pigs had reduced insulin sensitivity and higher relative mRNA abundance of lipogenic enzymes (ACACA, ACLY, FASN; P < 0.05) than lean pigs. The higher expression level of glucose-6-phosphate dehydrogenase (G6PD) combined with the trend (P < 0.10) of lower expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in fat pigs may explain part of their reduced insulin sensitivity. These results suggest that an increased BF is associated with reduced insulin sensitivity and greater expression of lipogenic enzymes in pig adipose tissue.

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 The Pal3 Promoter Sequence Is Critical for the Regulation of Human Renin Gene Transcription by Peroxisome Proliferator-Activated Receptor-γ

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4647-4657 ◽  
Author(s):  
Vladimir T. Todorov ◽  
Michael Desch ◽  
Thomas Schubert ◽  
Armin Kurtz
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Promoter Activity ◽  
Peroxisome Proliferator ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Renin ◽  
Pparγ Agonist ◽  
Renin Gene ◽  
Stimulation Of

We recently reported that human renin gene transcription is stimulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ in the renin-producing cell line Calu-6. The effect of PPARγ was mapped to two sequences in the renin promoter: a direct repeat hormone response element (HRE), which is related to the classical PPAR response element (PPRE) and a nonconsensus palindromic element with a 3-bp spacer (Pal3). We now find that PPARγ binds to the renin HRE. Neither the human renin HRE nor the consensus PPRE was sufficient to attain the maximal stimulation of renin promoter activity by the PPARγ agonist rosiglitazone. In contrast, the human renin Pal3 element mediates both the full PPARγ-dependent activation of transcription and the PPARγ-driven basal renin gene transcription. The human renin Pal3 sequence was found to selectively bind PPARγ and the retinoid X receptor-α from Calu-6 nuclear extracts. This is in contrast to the consensus PPRE, which can bind other nuclear proteins. PPARγ knockdown paradoxically did not attenuate the stimulation of the endogenous renin gene expression by rosiglitazone. Similarly, a deficiency of PPARγ did not attenuate the activation of the minimal human renin promoter, which contains the endogenous Pal3 motif. However, when the human renin Pal3 site was replaced by the consensus PPRE sequence, PPARγ knockdown abrogated the effect of rosiglitazone on renin promoter activity. Thus, the human renin Pal3 site appears to be critical for the PPARγ-dependent regulation of gene expression by mediating maximal transcription activation, particularly at the low cellular level of PPARγ.

scholarly journals The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis

2006 ◽  
Vol 20 (6) ◽  
pp. 1261-1275 ◽  
Author(s):  
Sarah Hummasti ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Target Genes ◽  
Biological Effects ◽  
Binding Domain ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus

Abstract Peroxisome proliferator-activated receptors (PPARγ, PPARα, and PPARδ) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARα and PPARδ regulate fatty acid catabolism, whereas PPARγ controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARγ confers the ability to promote adipocyte differentiation when fused to the PPARδ DNA binding domain and ligand binding domain, whereas the N terminus of PPARδ leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARγ. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

Troglitazone and pioglitazone interactions via PPAR-γ-independent and -dependent pathways in regulating physiological responses in renal tubule-derived cell lines

2007 ◽  
Vol 292 (3) ◽  
pp. C1137-C1146 ◽  
Author(s):  
Francesco Turturro ◽  
Robert Oliver ◽  
Ellen Friday ◽  
Itzhak Nissim ◽  
Tomas Welbourne
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Biological Effects ◽  
Cellular Growth ◽  
Glutamine Metabolism ◽  
Peroxisome Proliferator ◽  
Renal Tubules ◽  
Erk Activation ◽  
Ppar Γ

Troglitazone (Tro) and pioglitazone (Pio) activation of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-γ-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR-γ-dependent activation of PPAR response element-driven luciferase gene expression was observed with Pio at 1 μM but not Tro at 1 μM. On the other hand, PPAR-γ-independent P-ERK activation was observed with 5 μM Tro but not with Pio (5–20 μM). In addition, Pio (1–10 μM) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1–20 μM) did not. These results are consistent with three pathways through which glitazones may act in effecting metabolic processes (ammoniagenesis and gluconeogenesis) as well as cellular growth: 1) PPAR-γ-dependent and PPAR-γ-independent pathways, 2) P-ERK activation, and 3) mitochondrial AMPK activation. The pathways influence cellular acidosis and glucose and glutamine metabolism in a manner favoring reduced plasma glucose in vivo. In addition, significant interactions can be demonstrated that enhance some physiological processes (ammoniagenesis) and suppress others (ligand-mediated PPAR-γ gene expression). Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents.

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