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George E O Muscat - One of the best experts on this subject based on the ideXlab platform.
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nur77 regulates lipolysis in skeletal muscle cells evidence for cross talk between the β adrenergic and an orphan nuclear hormone Receptor pathway
Journal of Biological Chemistry, 2005Co-Authors: Megan A Maxwell, Angus Harding, Annika Stark, Mark E Cleasby, Gregory J Cooney, George E O MuscatAbstract:Abstract Skeletal muscle is a major mass peripheral tissue that accounts for ∼40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces β-adrenergic Receptor (β-AR)-mediated adaptive thermogenesis. β-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30–60 min of β-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone Receptor, Nur77. In contrast, the expression of other nuclear Receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase γ3, UCP3, CD36, Adiponectin Receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone Receptor and β-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
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nur77 regulates lipolysis in skeletal muscle cells evidence for cross talk between the beta adrenergic and an orphan nuclear hormone Receptor pathway
Journal of Biological Chemistry, 2005Co-Authors: Megan A Maxwell, Angus Harding, Annika Stark, Mark E Cleasby, Gregory J Cooney, George E O MuscatAbstract:Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces beta-adrenergic Receptor (beta-AR)-mediated adaptive thermogenesis. Beta-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30-60 min of beta-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone Receptor, Nur77. In contrast, the expression of other nuclear Receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase gamma3, UCP3, CD36, Adiponectin Receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone Receptor and beta-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
Zhixin Guo - One of the best experts on this subject based on the ideXlab platform.
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effect of telmisartan on the expression of Adiponectin Receptors and nicotinamide adenine dinucleotide phosphate oxidase in the heart and aorta in type 2 diabetic rats
Cardiovascular Diabetology, 2012Co-Authors: Zhixin Guo, Rong ZhangAbstract:Diabetic cardiovascular disease is associated with decreased Adiponectin and increased oxidative stress. This study investigated the effect of telmisartan on the expression of Adiponectin Receptor 2 (adipoR2) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits in the heart and the expression of Adiponectin Receptor 1 (adipoR1) in aorta in type 2 diabetic rats. Type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). Heart function, adipoR2, p22phox, NOX4, glucose transporter 4(GLUT4), monocyte chemoattractant protein-1(MCP-1) and connective tissue growth factor (CTGF)in the heart, and adipoR1, MCP-1 and nuclear factor kappa B (NF-κB) in aorta were analyzed in controls and diabetic rats treated with or without telmisartan (5mg/kg/d) by gavage for 12 weeks. Heart function, plasma and myocardial Adiponectin levels, the expression of myocardial adipoR2 and GLUT4 were significantly decreased in diabetic rats (P <0.05). The expression of myocardial p22phox, NOX4, MCP-1, and CTGF was significantly increased in diabetic rats (P <0.05). The expression of adipoR1 was decreased and the expression of MCP-1 and NF-κB was increased in the abdominal aorta in diabetic rats (P <0.05). Telmisartan treatment significantly attenuated these changes in diabetic rats (P <0.05). Our results suggest that telmisartan upregulates the expression of myocardial Adiponectin, its Receptor 2 and GLUT4. Simultaneously, it downregulates the expression of myocardial p22phox, NOX4, MCP-1, and CTGF, contributing so to the improvement of heart function in diabetic rats. Telmisartan also induces a protective role on the vascular system by upregulating the expression of adipoR1 and downregulating the expression of MCP-1 and NF-κB in the abdominal aorta in diabetic rats.
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cardiac expression of Adiponectin and its Receptors in streptozotocin induced diabetic rats
Metabolism-clinical and Experimental, 2007Co-Authors: Zhixin Guo, Zhengyuan Xia, Violet G Yuen, John H McneillAbstract:Adiponectin can improve both glucose metabolism and insulin resistance via the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway. Activated AMPK phosphorylates a variety of intracellular proteins, including acetyl coenzyme A carboxylase (ACC) that is involved in fatty acid oxidation. Adenosine monophosphate–activated protein kinase increases glucose transport by stimulating the translocation of glucose transporter 4 (GLUT4) to the sarcolemma in the heart. Adiponectin exerts its effect through Adiponectin Receptors, which are predominantly expressed in the liver and skeletal muscle. It is unknown whether the cardiac expression of Adiponectin and its Receptors is changed in diabetic rats. In the present study, we investigated the protein expression of Adiponectin and its Receptors in streptozotocin (STZ)–induced diabetic rat hearts. We also explored whether the levels of AMPK, ACC, and GLUT4 will be altered with the changed Adiponectin and its Receptors in STZ diabetic rat hearts. Plasma and cardiac Adiponectin levels were measured by radioimmunoassay. Plasma and cardiac interleukin 6 and plasma tumor necrosis factor α (TNF-α) were assayed by enzyme-linked immunosorbent assay. Cardiac Adiponectin Receptors, AMPK-α, ACC, GLUT4, and TNF-α were analyzed by Western blot in control and STZ diabetic rats. The plasma Adiponectin level was decreased, but the cardiac protein expression of Adiponectin Receptor 1 was increased in diabetic rats. There was no difference in the cardiac Adiponectin level and the cardiac Adiponectin Receptor 2 protein expression between control and diabetic rats. The phosphorylation of AMPK-α and protein expression of GLUT4 were decreased, but the phosphorylation of ACC was unchanged in diabetic rat hearts. Plasma and cardiac levels of interleukin 6 and TNF-α were increased in diabetic rats. In conclusion, STZ-induced diabetes up-regulates Adiponectin Receptors in the heart. Despite an increase in cardiac Adiponectin Receptor 1 expression, there is an increased cardiac inflammatory response and a decreased GLUT4 protein expression associated with a reduction in circulating Adiponectin.
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Effect of N-acetylcysteine on plasma Adiponectin and renal Adiponectin Receptors in streptozotocin-induced diabetic rats.
European journal of pharmacology, 2006Co-Authors: Zhixin Guo, Zhihua ZhaoAbstract:This study investigated the effect of N-acetylcysteine on plasma Adiponectin, renal Adiponectin Receptors, lipid metabolism and oxidative stress in streptozotocin-induced diabetic rats. Metabolic parameters, plasma Adiponectin level, renal protein expression of Adiponectin Receptors were analyzed in controls and diabetic rats treated with or without N-acetylcysteine in drinking water for 8 weeks. Plasma lipid, creatinine and free 5-F(2t)-isoprostane levels, urine protein excretion rate, mesangial matrix expansion index, and protein expression of renal connective tissue growth factor (CTGF) were increased in diabetic rats. The decreased plasma Adiponectin levels and renal protein expression of Adiponectin Receptor 1 were accompanied by the decreased renal phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-alpha (Thr172) and protein expression of phospho-acetyl coenzyme A carboxylase (ACC) (Ser79) which led to the increased renal triglyceride levels in diabetic rats. There was no difference in the protein expression of renal Adiponectin Receptor 2 between control and diabetic rats. N-acetylcysteine treatment attenuated the increased oxidative stress, plasma and renal lipids, urine protein excretion rate, mesangial matrix expansion index, and protein expression of renal CTGF, but did not affect plasma Adiponectin levels, renal protein expression of Adiponectin Receptor 1, phosphorylation of AMPK-alpha (Thr172) and renal protein expression of phospho-ACC (Ser79) in diabetic rats. These results suggested that the decreased plasma Adiponectin and renal Adiponectin Receptor 1 result in the increased renal triglyceride that stimulates renal CTGF expression leading to the renal hypertrophy and the deteriorated renal function in the diabetic rats. N-acetylcysteine treatment attenuates the increased oxidative stress, but has no effect on the decreased plasma Adiponectin and renal Adiponectin Receptor 1 in diabetic rats, indicating that oxidative stress may not contribute to the decreased plasma Adiponectin and renal Adiponectin Receptor 1 protein expression in diabetic rats.
Megan A Maxwell - One of the best experts on this subject based on the ideXlab platform.
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nur77 regulates lipolysis in skeletal muscle cells evidence for cross talk between the β adrenergic and an orphan nuclear hormone Receptor pathway
Journal of Biological Chemistry, 2005Co-Authors: Megan A Maxwell, Angus Harding, Annika Stark, Mark E Cleasby, Gregory J Cooney, George E O MuscatAbstract:Abstract Skeletal muscle is a major mass peripheral tissue that accounts for ∼40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces β-adrenergic Receptor (β-AR)-mediated adaptive thermogenesis. β-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30–60 min of β-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone Receptor, Nur77. In contrast, the expression of other nuclear Receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase γ3, UCP3, CD36, Adiponectin Receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone Receptor and β-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
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nur77 regulates lipolysis in skeletal muscle cells evidence for cross talk between the beta adrenergic and an orphan nuclear hormone Receptor pathway
Journal of Biological Chemistry, 2005Co-Authors: Megan A Maxwell, Angus Harding, Annika Stark, Mark E Cleasby, Gregory J Cooney, George E O MuscatAbstract:Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces beta-adrenergic Receptor (beta-AR)-mediated adaptive thermogenesis. Beta-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30-60 min of beta-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone Receptor, Nur77. In contrast, the expression of other nuclear Receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase gamma3, UCP3, CD36, Adiponectin Receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone Receptor and beta-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
Elisabet Stenervictorin - One of the best experts on this subject based on the ideXlab platform.
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circulating gonadotropins and ovarian Adiponectin system are modulated by acupuncture independently of sex steroid or β adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome
Molecular and Cellular Endocrinology, 2015Co-Authors: Manuel Maliqueo, Anna Benrick, Asif Alvi, Julia Johansson, Miao Sun, Fernand Labrie, Claes Ohlsson, Elisabet StenervictorinAbstract:Acupuncture with combined manual and low-frequency electrical stimulation, or electroacupuncture (EA), reduces endocrine and reproductive dysfunction in women with polycystic ovary syndrome (PCOS), likely by modulating sympathetic nerve activity or sex steroid synthesis. To test this hypothesis, we induced PCOS in rats by prepubertal implantation of continuous-release letrozole pellets (200 µg/day) or vehicle. Six weeks later, rats were treated for 5–6 weeks with low-frequency EA 5 days/week, subcutaneous injection of 17β-estradiol (2.0 µg) every fourth day, or a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg/kg) 5 days/week. Letrozole controls were handled without needle insertion or injected with sesame oil every fourth day. Estrous cyclicity, ovarian morphology, sex steroids, gonadotropins, insulin-like growth factor I, bone mineral density, and gene and protein expression in ovarian tissue were measured. Low-frequency EA induced estrous-cycle changes, decreased high levels of circulating luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio, decreased high ovarian gene expression of Adiponectin Receptor 2, and increased expression of Adiponectin Receptor 2 protein and phosphorylation of ERK1/2. EA also increased cortical bone mineral density. Propranolol decreased ovarian expression of Foxo3, Srd5a1, and Hif1a. Estradiol decreased circulating LH, induced estrous cycle changes, and decreased ovarian expression of Adipor1, Foxo3, and Pik3r1. Further, total bone mineral density was higher in the letrozole–estradiol group. Thus, EA modulates the circulating gonadotropin levels independently of sex steroids or β-adrenergic action and affects the expression of ovarian Adiponectin system.
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gene expression in subcutaneous adipose tissue differs in women with polycystic ovary syndrome and controls matched pair wise for age body weight and body mass index
Adipocyte, 2014Co-Authors: Louise Mannerasholm, Anna Benrick, Elisabet StenervictorinAbstract:Adipose tissue dysfunction may be a central factor in the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS). Gene expression in subcutaneous adipose tissue in PCOS and its relation to metabolic and endocrine features of the syndrome have been fragmentarily investigated. The aim was to assess in subcutaneous adipose tissue the expression of genes potentially associated with adipose tissue dysfunction and to explore their relation to features of the syndrome. Twenty-one women with PCOS (body mass index [BMI] 18.2–33.4 kg/m2) and 21 controls (BMI 19.2–31.7 kg/m2) were matched pair-wise for age, body weight, and BMI. Tissue biopsies were obtained to measure mRNA expression of 44 genes (TaqMan Low Density Array). Differential expression levels were correlated with BMI, glucose infusion rate (GIR), sex hormone binding globulin (SHBG), and sex steroids. In PCOS, expression of Adiponectin Receptor 2 (ADIPOR2), LPL, and twist-related protein 1 (TWIST1) was decreased, while expressio...
Jennifer R Rider - One of the best experts on this subject based on the ideXlab platform.
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tumor expression of Adiponectin Receptor 2 and lethal prostate cancer
Carcinogenesis, 2015Co-Authors: Jennifer R Rider, Michelangelo Fiorentino, Rachel S Kelly, Travis Gerke, Kristina M Jordahl, Jennifer A Sinnott, Edward Giovannucci, Massimo Loda, Lorelei A MucciAbstract:To investigate the role of Adiponectin Receptor 2 (AdipoR2) in aggressive prostate cancer we used immunohistochemistry to characterize AdipoR2 protein expression in tumor tissue for 866 men with prostate cancer from the Physicians' Health Study and the Health Professionals Follow-up Study. AdipoR2 tumor expression was not associated with measures of obesity, pathological tumor stage or prostate-specific antigen (PSA) at diagnosis. However, AdipoR2 expression was positively associated with proliferation as measured by Ki-67 expression quartiles (P-trend < 0.0001), with expression of fatty acid synthase (P-trend = 0.001), and with two measures of angiogenesis (P-trend < 0.1). An inverse association was observed with apoptosis as assessed by the TUNEL assay (P-trend = 0.006). Using Cox proportional hazards regression and controlling for age at diagnosis, Gleason score, year of diagnosis category, cohort and baseline BMI, we identified a statistically significant trend for the association between quartile of AdipoR2 expression and lethal prostate cancer (P-trend = 0.02). The hazard ratio for lethal prostate cancer for the two highest quartiles, as compared to the two lowest quartiles, of AdipoR2 expression was 1.9 (95% confidence interval [CI]: 1.2-3.0). Results were similar when additionally controlling for categories of PSA at diagnosis and Ki-67 expression quartiles. These results strengthen the evidence for the role of AdipoR2 in prostate cancer progression.
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modification of the association between obesity and lethal prostate cancer by tmprss2 erg
Journal of the National Cancer Institute, 2013Co-Authors: Andreas Pettersson, Jennifer R Rider, Michelangelo Fiorentino, Allison Meisner, Richard Flavin, Edward C Stack, Stephen Finn, Rebecca E Graff, Kathryn L Penney, Elizabeth NuttallAbstract:Prostate cancer patients who are overweight have greater risk of disease recurrence and cancer-specific mortality (1,2). In the United States, 238590 men will be diagnosed with prostate cancer in 2013, and two-thirds of the adult male population is overweight or obese (3,4). Thus, understanding the mechanisms linking excess bodyweight with worse prostate cancer outcomes has important public health implications. Obesity deregulates multiple pathways that could influence disease outcomes. For example, circulating levels of insulin, free insulin growth factor 1 (IGF-1), Adiponectin, and sex hormones are altered in obese vs normal-weight men (5,6). The common gene fusion TMPRSS2:ERG is present in half of prostate cancers (7,8). TMPRSS2 is regulated by androgens and possibly estrogens (9), and the oncogene ERG is a member of the ETS transcription factor family. Its discovery in 2005 was notable both because it was the first identification of a common gene fusion in a common solid tumor and because it represents a model of hormonal regulation of an oncogene. Based on experimental and clinical data, TMPRSS2:ERG-positive tumors may define a distinct subgroup of prostate cancers (8). Gene fusions involving ETS transcription factors are also present in other cancers. Notably, the ETS fusion EWS/FLI-1 occurs in 90% of Ewing sarcomas and is linked with increased IGF-1 Receptor (IGF-1R) activity (10,11). Given its influence on several hormonal pathways (5,6), obesity could potentially interact with TMPRSS2:ERG to differentially impact prostate cancer outcomes. In this study, we examined in a cohort of 1243 US men with prostate cancer whether the associations of body mass index (BMI; kg/m2) and waist circumference with prostate cancer recurrence and death differ among men whose tumors overexpressed ERG [a marker of TMPRSS2:ERG (12)] compared with men whose tumors did not. We also explored whether tumor expression of key metabolic proteins IGF-1R, insulin Receptor (IR), Adiponectin Receptor 2 (AdipoR2), and fatty acid synthase (FASN) differs in ERG-positive vs ERG-negative tumors.