Agouti regulates adipocyte transcription factors

2001 ◽  
Vol 280 (4) ◽  
pp. C954-C961 ◽  
Author(s):  
Randall L. Mynatt ◽  
Jacqueline M. Stephens
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Paracrine Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Skeletal Mass ◽  
Ppar Γ ◽  
Obesity And Diabetes

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agoutiexpression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-γ protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-γ.

Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size

2005 ◽  
Vol 288 (1) ◽  
pp. E117-E124 ◽  
Author(s):  
Mayumi Takahashi ◽  
Yasutomi Kamei ◽  
Osamu Ezaki
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
Type Ii Diabetes ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Fatty Acid Binding ◽  
Enhanced Expression

Obesity is a common and serious metabolic disorder in the developed world that is occasionally accompanied by type II diabetes, atherosclerosis, hypertension, and hyperlipidemia. We have found that mesoderm-specific transcript (Mest)/paternally expressed gene 1 (Peg1) gene expression was markedly enhanced in white adipose tissue of mice with diet-induced and genetically caused obesity/diabetes but not with streptozotocin-induced diabetes, which does not cause obesity. Administration of pioglitazone, a drug for type II diabetes and activator of peroxisome proliferator-activated receptor (PPAR)γ, in obese db/ db mice reduced the enhanced expression of Mest mRNA in adipose tissue, concomitant with an increase in body weight and a decrease in the size of adipose cells. Ectopic expression of Mest in 3T3-L1 cells caused increased gene expression of adipose markers such as PPARγ, CCAAT/enhancer binding protein (C/EBP)α, and adipocyte fatty acid binding protein (aP)2. In transgenic mice overexpressing Mest in adipose tissue, enhanced expression of the adipose genes was observed. Moreover, adipocytes were markedly enlarged in the transgenic mice. Thus Mest appears to enlarge adipocytes and could be a novel marker of the size of adipocytes.

scholarly journals Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities

2020 ◽  
Vol 12 (2) ◽  
pp. 85-101
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Common Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Brown Adipose ◽  
Key Factor ◽  
Beige Fat

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function.CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige.SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

Endotoxin downregulates peroxisome proliferator-activated receptor-γ via the increase in TNF-α release

2008 ◽  
Vol 294 (1) ◽  
pp. R84-R92 ◽  
Author(s):  
Mian Zhou ◽  
Rongqian Wu ◽  
Weifeng Dong ◽  
Asha Jacob ◽  
Ping Wang
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Cecal Ligation ◽  
Polymyxin B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Ppar Γ ◽  
Tnf Α ◽  
A Cell

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR-γ gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR-γ is altered in sepsis and, if so, whether LPS directly downregulates PPAR-γ. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR-γ gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR-γ gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR-γ levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR-γ downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR-γ expression. We found that circulating levels of TNF-α still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR-γ expression is TNF-α dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-α. TNF-α significantly attenuated PPAR-γ gene expression in KCs. Although LPS decreased PPAR-γ in KCs, the downregulatory effect of LPS was blocked by the addition of TNF-α-neutralizing antibodies. Furthermore, the administration of TNF-α-neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR-γ in sepsis. We, therefore, conclude that LPS downregulates PPAR-γ expression during sepsis via an increase in TNF-α release.

scholarly journals PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

2021 ◽  
Author(s):  
Jorge-Luis Torres ◽  
Ricardo Usategui-Martín ◽  
Lourdes Hernández-Cosido ◽  
Edgar Bernardo ◽  
Laura Manzanedo-Bueno ◽  
...  
Keyword(s):  
Weight Loss ◽  
Adipose Tissue ◽  
Sleeve Gastrectomy ◽  
Morbidly Obese ◽  
Peroxisome Proliferator ◽  
Obese Patients ◽  
Peroxisome Proliferator Activated Receptor ◽  
Clinical Variables ◽  
Ppar Γ ◽  
Obese Subjects

Abstract Background The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and Methods. We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. Results We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. Conclusion PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgery.

scholarly journals Characterization of the human, mouse and rat PGC1beta (peroxisome-proliferator-activated receptor-gamma co-activator 1beta) gene in vitro and in vivo

2003 ◽  
Vol 373 (1) ◽  
pp. 155-165 ◽  
Author(s):  
Aline MEIRHAEGHE ◽  
Vivion CROWLEY ◽  
Carol LENAGHAN ◽  
Christopher LELLIOTT ◽  
Kath GREEN ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Thyroid Hormone Receptor ◽  
Ectopic Expression ◽  
Cdna Libraries ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

PGC1α is a co-activator involved in adaptive thermogenesis, fatty-acid oxidation and gluconeogenesis. We describe the identification of several isoforms of a new human PGC1α homologue, cloned independently and named PGC1β. The human PGC1β gene is localized to chromosome 5, has 13 exons and spans more than 78 kb. Two different 5′ and 3′ ends due to differential splicing were identified by rapid amplification of cDNA ends PCR and screening of human cDNA libraries. We show that PGC1β variants in humans, mice and rats are expressed predominantly in heart, brown adipose tissue, brain and skeletal muscle. PGC1β expression, unlike PGC1α, is not up-regulated in brown adipose tissue in response to cold or obesity. Fasting experiments showed that PGC1α, but not PGC1β, is induced in liver and this suggests that only PGC1α is involved in the hepatic gluconeogenesis. No changes in PGC1β gene expression were observed associated with exercise. Human PGC1β-1a and −2a isoforms localized to the cell nucleus and, specifically, the isoform PGC1β-1a co-activated peroxisome-proliferator-activated receptor-γ, -α and the thyroid hormone receptor β1. Finally, we show that ectopic expression PGC1β leads to increased mitochondrial number and basal oxygen consumption. These results suggest that PGC1β may play a role in constitutive adrenergic-independent mitochondrial biogenesis.

scholarly journals Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 394
Author(s):  
Selin Gencer ◽  
Yvonne Döring ◽  
Yvonne Jansen ◽  
Soyolmaa Bayasgalan ◽  
Olga Schengel ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Cholesterol Content ◽  
Metabolic Effects ◽  
Peroxisome Proliferator ◽  
Lipid Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Deficient Mice

Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe−/− mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.

Proteomic study of periovarian adipose tissue in 17β-estradiol-treated and untreated ovariectomized rats

2016 ◽  
Vol 94 (2) ◽  
pp. 167-175 ◽  
Author(s):  
Emilia Amengual-Cladera ◽  
Gabriela Capllonch-Amer ◽  
Isabel Lladó ◽  
Magdalena Gianotti ◽  
Ana M. Proenza
Keyword(s):  
Adipose Tissue ◽  
Mitochondrial Function ◽  
Corn Oil ◽  
Ovariectomized Rats ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Inflammatory Protein ◽  
17Β Estradiol

Taking into account the sexual dimorphism previously found in white adipose tissue (WAT) regarding mitochondrial function and biogenesis, as well as insulin sensitivity, the aim of this study was to go further into the role of sex hormones in this dimorphism. To achieve this objective, we used ovariectomized rats and performed a screening by means of proteomic analyses of the periovarian WAT, combined with a study of the protein levels of specific factors involved in mitochondrial function. Rats were ovariectomized at 5 weeks of age and subcutaneously injected every 48 h with corn-oil (OVX group) or with 17β-estradiol (E2, 10 μg/kg body mass; OVX + E2 group) for 4 weeks prior to sacrifice. Beside proteomic analysis, protein levels of Transcription Factor A, Mitochondrial (TFAM), cytochrome oxidase (COX)II, and COXIV were determined by Western blot, and mRNA levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, ERα, ERβ, lipoprotein lipase (LPL), peroxisome proliferator-activated receptor-γ (PPARγ), and adiponectin were quantified by real-time PCR. Our results show that ovariectomy leads to an increase in anabolic processes and inflammatory protein levels as well as to a decrease in some of the markers of mitochondrial function, which are restored, at least in part, by E2 supplementation. Indeed, this E2 supplementation seems to be counteracted by a decline in ERα and in the ERα to ERβ ratio values that could be directed to avoid an over-stimulation of the E2 signaling pathway, given the possibility of an activation of extra-gonadal steroid biosynthetic pathways.

scholarly journals Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system

2017 ◽  
Vol 312 (6) ◽  
pp. R1029-R1038 ◽  
Author(s):  
G. Angela Massmann ◽  
Jie Zhang ◽  
Won Joon Seong ◽  
Minhyoung Kim ◽  
Jorge P. Figueroa
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Mrna Expression ◽  
Renin Angiotensin System ◽  
Female Offspring ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pregnant Sheep

Exposure to glucocorticoids in utero is associated with changes in organ function and structure in the adult. The aims of this study were to characterize the effects of antenatal exposure to glucocorticoids on glucose handling and the role of adipose tissue. Pregnant sheep received betamethasone (Beta, 0.17 mg/kg) or vehicle 24 h apart at 80 days of gestation and allowed to deliver at term. At 9 mo, male and female offspring were fed at either 100% of nutritional allowance (lean) or ad libitum for 3 mo (obese). At 1 yr, they were chronically instrumented under general anesthesia. Glucose tolerance was evaluated using a bolus of glucose (0.25 g/kg). Adipose tissue was harvested after death to determine mRNA expression levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) 1, ACE2, and peroxisome proliferator-activated receptor γ (PPAR-γ). Data are expressed as means ± SE and analyzed by ANOVA. Sex, obesity, and Beta exposure had significant effects on glucose tolerance and mRNA expression. Beta impaired glucose tolerance in lean females but not males. Superimposed obesity worsened the impairment in females and unmasked the defect in males. Beta increased ACE1 mRNA in females and males and AGT in females only ( P < 0.05 by three-way ANOVA). Obesity increased AGT in females but had no effect on ACE1 in either males or females. PPAR-γ mRNA exhibited a significant sex ( F = 42.8; P < 0.01) and obesity ( F = 6.9; P < 0.05) effect and was significantly higher in males ( P < 0.01 by three-way ANOVA). We conclude that adipose tissue may play an important role in the sexually dimorphic response to antenatal glucocorticoids.

Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue

2005 ◽  
Vol 288 (5) ◽  
pp. E957-E964 ◽  
Author(s):  
Galina Apostolova ◽  
Roberto A. S. Schweizer ◽  
Zoltan Balazs ◽  
Radina M. Kostadinova ◽  
Alex Odermatt
Keyword(s):  
Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Promising Target ◽  
Pparγ Agonist ◽  
Treatment Of Obesity ◽  
Underlying Mechanisms

Dehydroepiandrosterone (DHEA) exerts beneficial effects on blood glucose levels and insulin sensitivity in obese rodents and humans, resembling the effects of peroxisome proliferator-activated receptor-γ (PPARγ) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which is currently considered as a promising target for the treatment of obesity and diabetes. Using differentiated 3T3-L1 adipocytes, we show that DHEA causes downregulation of 11β-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPARγ agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11β-HSD1. These findings were confirmed in white adipose tissue and in liver from DHEA-treated C57BL/6J mice. Analysis of the transcription factors involved in the DHEA-dependent regulation of 11β-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBPα, a potent activator of 11β-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBPβ and C/EBPδ, attenuating the effect of C/EBPα, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPARα and downregulating leptin, thereby contributing to the reduced expression of 11β-HSD1. In summary, we provide evidence that some of the anti-diabetic effects of DHEA may be caused through inhibition of the local amplification of glucocorticoids by 11β-HSD1 in adipose tissue.

scholarly journals The Ubiquitin Ligase Siah2 Regulates PPARγ Activity in Adipocytes

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1206-1218 ◽  
Author(s):  
Gail Kilroy ◽  
Heather Kirk-Ballard ◽  
Lauren E. Carter ◽  
Z. Elizabeth Floyd
Keyword(s):  
Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Ppar Γ ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
Seven In Absentia ◽  
The Relationship

Moderate reductions in peroxisome proliferator-activated receptor (PPAR)γ levels control insulin sensitivity as effectively as activation of PPARγ in adipocytes by the thiazolidinediones. That observation suggests that PPARγ activity can be regulated by modulating the amount of PPARγ protein in adipocytes. Activation of PPARγ in adipocytes is linked to changes in PPARγ protein levels via increased degradation of PPARγ proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPARγ is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPARγ. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPARγ protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPARγ ubiquitylation and ligand-dependent activation of PPARγ in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPARγ interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPARγ protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPARγ activation in adipocytes.

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