Hepatic ADTRP overexpression does not influence lipid and glucose metabolism

2021 ◽  
Author(s):  
Merel Defour ◽  
Michel van Weeghel ◽  
Jill Hermans ◽  
Sander Kersten
Keyword(s):  
Fatty Acids ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Plasma Cholesterol ◽  
Fatty Acid Esters ◽  
Plasma Metabolites ◽  
Peroxisome Proliferator ◽  
Serine Hydrolase ◽  
Glucose Levels ◽  
Metabolism Regulation

The peroxisome proliferator activated receptors (PPARs) are a group of transcription factors belonging to the nuclear receptor superfamily. Since most target genes of either PPARs are implicated in lipid and glucose metabolism, regulation by PPARs could be used as a screening tool to identify novel genes involved in lipid or glucose metabolism. Here, we identify Adtrp, a serine hydrolase enzyme that was reported to catalyze the hydrolysis of fatty acid esters of hydroxy fatty acids (FAHFAs), as a novel PPAR-regulated gene. Adtrp was significantly upregulated by PPARα activation in mouse primary hepatocytes, liver slices, and whole liver. In addition, Adtrp was upregulated by PPARγ activation in 3L3-L1 adipocytes and in white adipose tissue. ChIP-SEQ identified a strong PPAR binding site in the immediate upstream promoter of the Adtrp gene. Adenoviral-mediated hepatic overexpression of Adtrp in diet-induced obese mice caused a modest increase in plasma non-esterified fatty acids but did not influence diet-induced obesity, liver triglyceride levels, liver lipidomic profiles, liver transcriptomic profiles, and plasma cholesterol, triglycerides, glycerol, and glucose levels. Moreover, hepatic Adtrp overexpression did not lead to significant changes in FAHFA levels in plasma or liver and did not influence glucose and insulin tolerance. Finally, hepatic overexpression of Adtrp did not influence liver triglycerides and levels of plasma metabolites after a 24h fast. Taken together, our data suggest that despite being a PPAR-regulated gene, hepatic Adtrp does not seem to play a major role in lipid and glucose metabolism and does not regulate FAHFA levels.

scholarly journals Branched-Chain Fatty Acids as Mediators of the Activation of Hepatic Peroxisome Proliferator-Activated Receptor Alpha by a Fungal Lipid Extract

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1259 ◽  
Author(s):  
Garima Maheshwari ◽  
Robert Ringseis ◽  
Gaiping Wen ◽  
Denise K. Gessner ◽  
Johanna Rost ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Reporter Gene ◽  
Target Genes ◽  
Reporter Gene Assay ◽  
Lipid Extract ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Branched Chain Fatty Acids ◽  
Gene Assay ◽  
Branched Chain

The study aimed to test the hypothesis that monomethyl branched-chain fatty acids (BCFAs) and a lipid extract of Conidiobolus heterosporus (CHLE), rich in monomethyl BCFAs, are able to activate the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha). Rat Fao cells were incubated with the monomethyl BCFAs 12-methyltridecanoic acid (MTriA), 12-methyltetradecanoic acid (MTA), isopalmitic acid (IPA) and 14-methylhexadecanoic acid (MHD), and the direct activation of PPARalpha was evaluated by reporter gene assay using a PPARalpha responsive reporter gene. Furthermore, Fao cells were incubated with different concentrations of the CHLE and PPARalpha activation was also evaluated by using the reporter gene assay, and by determining the mRNA concentrations of selected PPARalpha target genes by real-time RT-PCR. The reporter gene assay revealed that IPA and the CHLE, but not MTriA, MHD and MTA, activate the PPARalpha responsive reporter gene. CHLE dose-dependently increased mRNA concentrations of the PPARalpha target genes acyl-CoA oxidase (ACOX1), cytochrome P450 4A1 (CYP4A1), carnitine palmitoyltransferase 1A (CPT1A) and solute carrier family 22 (organic cation/carnitine transporter), member 5 (SLC22A5). In conclusion, the monomethyl BCFA IPA is a potent PPARalpha activator. CHLE activates PPARalpha-dependent gene expression in Fao cells, an effect that is possibly mediated by IPA.

scholarly journals The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice

2012 ◽  
Vol 32 (6) ◽  
pp. 619-629 ◽  
Author(s):  
Chanjuan Hao ◽  
Xuejia Cheng ◽  
Hongfei Xia ◽  
Xu Ma
Keyword(s):  
Target Genes ◽  
Adipocyte Differentiation ◽  
Cell Model ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Ethylhexyl Phthalate

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.

Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver

2010 ◽  
Vol 41 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Linda M. Sanderson ◽  
Mark V. Boekschoten ◽  
Beatrice Desvergne ◽  
Michael Müller ◽  
Sander Kersten
Keyword(s):  
Gene Expression ◽  
Mouse Liver ◽  
Target Genes ◽  
Glucose Utilization ◽  
Plasma Cholesterol ◽  
Transcriptional Profiling ◽  
Regulation Of Gene Expression ◽  
Lipoprotein Metabolism ◽  
Peroxisome Proliferator ◽  
Fed State

Little is known about the role of the transcription factor peroxisome proliferator-activated receptor (PPAR) β/δ in liver. Here we set out to better elucidate the function of PPARβ/δ in liver by comparing the effect of PPARα and PPARβ/δ deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARα and PPARβ/δ deletion was similar, whereas in fasted state the effect of PPARα deletion was much more pronounced, consistent with the pattern of gene expression of PPARα and PPARβ/δ. Minor overlap was found between PPARα- and PPARβ/δ-dependent gene regulation in liver. Pathways upregulated by PPARβ/δ deletion were connected to innate immunity and inflammation. Pathways downregulated by PPARβ/δ deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARβ/δ−/− mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARβ/δ target genes. In contrast to PPARα−/− mice, no changes in plasma free fatty acid, plasma β-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPARβ/δ−/− mice. Our data indicate that PPARβ/δ governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver.

scholarly journals Effects of Baccharin Isolated from Brazilian Green Propolis on Adipocyte Differentiation and Hyperglycemia in ob/ob Diabetic Mice

2021 ◽  
Vol 22 (13) ◽  
pp. 6954
Author(s):  
Akio Watanabe ◽  
Marília Oliveira de Almeida ◽  
Yusuke Deguchi ◽  
Ryuzo Kozuka ◽  
Caroline Arruda ◽  
...  
Keyword(s):  
Target Genes ◽  
Adipocyte Differentiation ◽  
Biological Activities ◽  
Intraperitoneal Administration ◽  
Peroxisome Proliferator ◽  
Cinnamic Acid Derivative ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Brazilian Green Propolis

Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.

scholarly journals In Vivo Analysis of miR-34a Regulated Glucose Metabolism Related Genes in Megalobrama amblycephala

2018 ◽  
Vol 19 (8) ◽  
pp. 2417 ◽  
Author(s):  
Ling-Hong Miao ◽  
Yan Lin ◽  
Xin Huang ◽  
Wen-Jing Pan ◽  
Qun-Lan Zhou ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Janus Kinase ◽  
Megalobrama Amblycephala ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Downstream Target

The Megalobrama amblycephala (M. amblycephala) is one of the most important economic freshwater fish in China. The molecular mechanism under the glucose intolerance responses which affects the growth performance and feed utilization is still confused. miR-34a was reported as a key regulator in the glucose metabolism, but how did the miR-34a exert its function in the metabolism of glucose/insulin in M. amblycephala was still unclear. In this study, we intraperitoneally injected the miR-34a inhibitor (80 nmol/100 g body weight) into M. amblycephala (fed with high starch diet, 45% starch) for 12 h, and then analyzed the gene expression profiling in livers by RNA-seq. The results showed that miR-34a expression in M. amblycephala livers was inhibited by injection of miR-34a inhibitor, and a total of 2212 differentially expressed genes (DEGs) were dysregulated (including 1183 up- and 1029 downregulated DEGs). Function enrichment analysis of DEGs showed that most of them were enriched in the peroxisome proliferator-activated receptor (PPAR), insulin, AMP-activated protein kinase (AMPK) and janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways, which were all associated with the glucose/lipid metabolic and biosynthetic processes. In addition, we examined and verified the differential expression levels of some genes involved in AMPK signaling pathway by qRT-PCR. These results demonstrated that the inhibition of miR-34a might regulate glucose metabolism in M. amblycephala through downstream target genes.

scholarly journals Hepatic Ago2 Regulates PPARα for Oxidative Metabolism Linked to Glycemic Control in Obesity and Post Bariatric Surgery

Endocrinology ◽  
2021 ◽  
Vol 162 (4) ◽  
Author(s):  
Jashdeep Bhattacharjee ◽  
Vishnupriya J Borra ◽  
Esam S B Salem ◽  
Cai Zhang ◽  
Kazutoshi Murakami ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oxidative Metabolism ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Functions ◽  
Mitochondrial Oxidation ◽  
Main Component

Abstract Argonaute 2 (Ago2) is the main component of the RNA-induced silencing complex. We recently showed that liver-specific Ago2-deficiency in mice (L-Ago2 knockout [KO] mice) enhances mitochondrial oxidation and alleviates obesity-associated pathophysiology. However, the precise mechanisms behind the role of hepatic Ago2 in regulating the mitochondrial oxidation associated with glucose metabolism are still unclear. Here, we show that hepatic Ago2 regulates the function of peroxisome proliferator–activated receptor α (PPARα) for oxidative metabolism. In both genetically and diet-induced severe obese conditions, L-Ago2 KO mice developed obesity and hepatic steatosis but exhibited improved glucose metabolism accompanied by lowered expression levels of pathologic microRNAs (miRNAs), including miR-802, miR-103/107, and miR-152, and enhanced expression of PPARα and its target genes regulating oxidative metabolism in the liver. We then investigated the role of hepatic Ago2 in the outcomes of vertical sleeve gastrectomy (VSG) in which PPARα plays a crucial role in a drastic transcription reprogram associated with improved glycemia post VSG. Whereas VSG reduced body weight and improved fatty liver in wild-type mice, these effects were not observed in hepatic Ago2-deficient mice. Conversely, glucose metabolism was improved in a hepatic Ago2-dependent manner post VSG. Treating Ago2-deficient primary hepatocytes with WY-14643, a PPARα agonist, showed that Ago2-deficiency enhances sensitivity to WY-14643 and increases expression of PPARα target genes and mitochondrial oxidation. Our findings suggest that hepatic Ago2 function is intrinsically associated with PPARα that links Ago2-mediated RNA silencing with mitochondrial functions for oxidation and obesity-associated pathophysiology.

scholarly journals Rhein Reduces Fat Weight indb/dbMouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγSignaling

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yu Zhang ◽  
Shengjie Fan ◽  
Na Hu ◽  
Ming Gu ◽  
Chunxiao Chu ◽  
...  
Keyword(s):  
Target Genes ◽  
Fasting Blood Glucose ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Rheum Palmatum ◽  
Diet Induced Obesity ◽  
Blood Glucose Levels ◽  
Underlying Mechanisms

Rheum palmatumhas been used most frequently in the weight-reducing formulae in traditional Chinese medicine. However, the components ofRheum palmatumthat play the antiobesity role are still uncertain. Here, we tested the weight-reducing effect of two majorRheum palmatumcompounds ondb/dbmouse. We found that rhein (100 mg kg−1 day−1), but not emodin, reduced the fat weight indb/dbmouse. Using diet-induced obese (DIO) C57BL/6 mice, we identified that rhein blocked high-fat diet-induced obesity, decreased fat mass and the size of white and brown adipocytes, and lowered serum cholesterol, LDL cholesterol, and fasting blood glucose levels in the mice. To elucidate the underlying mechanisms, we used reporter assay and gene expression analysis and found that rhein inhibited peroxisome proliferator-activated receptorγ(PPARγ) transactivity and the expression of its target genes, suggesting that rhein may act as a PPARγantagonist. Our data indicate that rhein may be a promising choice for antiobesity therapy.

scholarly journals Calcium and Magnesium Urinary Excretion in Dairy Cows with Different Fee of Glucose Metabolization

2018 ◽  
Vol 46 (1) ◽  
pp. 7
Author(s):  
Elizabeth Schwegler ◽  
Paula Montagner ◽  
Eduardo Schmitt ◽  
Augusto Schneider ◽  
Marina Menoncin Weschenfelder Rohenkohl ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Glucose Metabolism ◽  
Dairy Cows ◽  
Milk Production ◽  
Post Partum ◽  
Glucose Levels ◽  
Metabolism Rate ◽  
Esterified Fatty Acids ◽  
Low Glucose

Background: The post-partum period in dairy cows is accompanied by a low glucose metabolism in adipose tissue and skeletal muscle tissue, being glucose conducted to the milk production. In humans, low glucose metabolism is associated with metabolic syndromes, the high glucose levels reduce tubular reabsorption of Magnesium (Mg) and Calcium (Ca), leading to hypomagnesemia and hypocalcemia. These minerals are important to the dairy cow, as their decrease leads to diseases. The aim of this study was to evaluate the relationship between glucose metabolism rate with the urinary excretion of Ca and Mg in multiparous dairy cows during the post-partum period.Materials, Methods & Results: Twenty dairy cows were used from a commercial farm southern Brazil, in the semi-extensive system. Glucose tolerance tests were performed (TTG) on day 9 relative to calving. The cows were categorized into three groups according to the glucose metabolism rate (area under the glucose curve, glucose half-life and glucose consumption rate): High Glucose Metabolization (GA); Intermediate Glucose Metabolizing (GI); and Low Glucose Metabolization (GL). Blood and urine samples were collected on days 0, + 3, + 6, + 9, +16 and +2 3 in relation to calving for to determine the levels of Ca, Mg, insulin (Ins), non-esterified fatty acids (NEFA) and Glu. In urine was evaluated the excretion of Ca and Mg. The cows were milked twice a day (at 3:00 a.m. and 3:00 p.m.) and the milk yield (kg/cow) was recorded daily and averages were generated every five days from day 15 to day 60 postpartum. The statistical analyses were performed with the MIXED procedure to assess the main effect of group, time (in days) and their interaction by using version 9.2 SAS software. The influence of the different rates of glucose metabolism on milk production was observed, the GB group had a production than GH group (30.88 ± 1.44 kg vs 23.96 ± 1.43 kg, P < 0.01), but did not differ from GI. The GL group showed higher levels of Glu compared to GA (P < 0.05). The plasma Ca levels were higher in GL (P < 0.05) compared with GH. The NEFA, insulin, and excretion of minerals did not differ between groups (P > 0.05).Discussion: The low glucose metabolism in humans causes an increase in the excretion of Ca and Mg urine, however, in the animals studied, these changes were not observed. This result can be attributed to the fact that insulin resistance is transitory in dairy cattle. The higher glucose levels in the GL group are related due to the lower capacity of glucose entry in the peripheral tissues (adipose and skeletal muscle), which reflected in the higher milk production observed this group. However, the higher calcium concentrations were not expected, since the release of insulin by β-pancreatic cells is dependent on calcium. Possibly, these higher calcium levels in GB, are related to higher milk production, requiring a greater amount of calcium for the production of casein, increasing bone mobilization, intestinal absorption. The energy metabolites, non-esterified fatty acids and insulin, did not differ between groups, suggesting that the animals did not present different metabolic conditions. We conclude that multiparous dairy cows with low glucose metabolism rate (GB) have higher levels of glucose after delivery and increased milk production. The metabolism rate of glucose did not influence the excretion of the Ca and Mg minerals.

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

2012 ◽  
Vol 302 (12) ◽  
pp. E1461-E1471 ◽  
Author(s):  
Takeshi Kobayashi ◽  
Ko Fujimori
Keyword(s):  
Fatty Acids ◽  
Target Genes ◽  
Mrna Level ◽  
Peroxisome Proliferator ◽  
Long Chain Fatty Acids ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipogenic Genes ◽  
Pparγ Agonist ◽  
Long Chain ◽  
Chain Fatty Acids

Here, we show that Elovl3 (elongation of very long-chain fatty acids 3) was involved in the regulation of the progression of adipogenesis through activation of peroxisome proliferator-activated receptor (PPAR)γ in mouse adipocytic 3T3-L1 cells. The expression of the Elovl3 gene increased during adipogenesis, the expression pattern of which was similar to that of the PPARγ gene. Troglitazone, a PPARγ agonist, enhanced Elovl3 expression in adipocytes, as it did that of other PPARγ target genes. Promoter-reporter analysis demonstrated that three PPAR-responsive elements in the Elovl3 gene promoter had the potential to activate its expression in 3T3-L1 cells. Moreover, a chromatin immunoprecipitation assay revealed that PPARγ bound these PPAR-responsive elements of the Elovl3 promoter. When the Elovl3 mRNA level was suppressed by its siRNAs, the level of intracellular triglycerides was significantly decreased, and the expression levels of adipogenic, lipolytic, and lipogenic genes were also repressed. In a mammalian two-hybrid assay, C18:1 and C20:1 very long-chain fatty acids (VLCFAs), which are the products of Elovl3 and activated PPARγ function. In addition, these same VLCFAs could prevent the Elovl3 siRNA-mediated suppression of adipogenesis by enhancing the expression of adipogenic, lipolytic, and lipogenic genes in adipocytes. Moreover, this VLCFAs-mediated activation was repressed by a PPARγ antagonist. These results indicate that the expression of the Elovl3 gene was activated by PPARγ during adipogenesis. Elovl3-produced C18:1 and C20:1 VLCFAs acted as agonists of PPARγ in 3T3-L1 cells. Thus, the Elovl3-PPARγ cascade is a novel regulatory circuit for the regulation of adipogenesis through improvement of PPARγ function in adipocytes.

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