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Herbert Tilg - One of the best experts on this subject based on the ideXlab platform.
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adiponectin key player in the adipose tissue liver crosstalk
Current Medicinal Chemistry, 2012Co-Authors: Alexander R Moschen, V Wieser, Herbert TilgAbstract:The adipose tissue has recently emerged as an important endocrine organ releasing numerous mediators including Adipocytokines, classical cytokines and others. Adiponectin, one of the major products of adipocytes, is a prototypic anti-diabetic Adipocytokine, the actions of which are mainly exerted by the activation of AMP-activated kinase and peroxisome proliferator-activated receptor alpha. This Adipocytokine is one of the most abundant circulating (adipo)cytokines in health. Non-alcoholic fatty liver disease (NAFLD), the major reason for abnormal liver functions in the western world, is commonly associated with obesity, insulin resistance and decreased adiponectin serum levels. Adiponectin has many anti-inflammatory activities and suppresses tumour necrosis factor-alpha (TNF), a cytokine of key importance in NAFLD. The anti-inflammatory effects of adiponectin are also exerted by induction of the anti-inflammatory cytokines interleukin-10 (IL-10) or IL-1 receptor antagonist and up-regulation of heme-oxygenase-1. Whereas the liver probably is not a relevant source of circulating adiponectin, it is a major target organ for many adiponectin effects. Adiponectin is able to regulate steatosis, insulin resistance, inflammation and fibrosis. NAFLD is also associated with decreased liver expression of the two adiponectin receptors (AdipoR1 and 2) thereby contributing to a state of hepatic adiponectin resistance. In contrast, most other liver diseases especially in advanced disease states exhibit increased adiponectin serum levels with highest levels observed in cirrhosis. Targeting adiponectin could evolve as a major treatment concept especially for fatty liver diseases in the future.
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anti inflammatory effects of excessive weight loss potent suppression of adipose interleukin 6 and tumour necrosis factor α expression
Gut, 2010Co-Authors: Alexander R Moschen, Arthur Kaser, Clemens Molnar, Helmut Weiss, Ivo Graziadei, Susanne Kaser, Christoph Ebenbichler, Sabine Geiger, Herbert TilgAbstract:Objective Severe obesity is a chronic inflammatory disease where various cytokines/Adipocytokines play a key role. Pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumour necrosis factor-α (TNFα) are produced by human adipose tissue dependent on the degree of obesity. Mouse studies suggest a key role of adipose tissue-derived IL-6 in hepatic insulin resistance via modification of liver suppressor of cytokine signalling 3 (SOCS-3) expression. Design and methods We examined the effect of excessive weight loss on systemic levels, subcutaneous and visceral adipose tissue and liver expression of IL-6 and TNFα in 20 severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB). Furthermore, we studied liver expression of SOCS3, an important regulator of insulin resistance, and fat tissue expression of the anti-inflammatory Adipocytokine adiponectin and its receptors. Serum and tissue samples were collected before and 6 months after LAGB surgery. Results IL-6/TNFα mRNA expression before weight loss were similar in subcutaneous and visceral adipose tissue and much higher compared to hepatic expression. Subcutaneous adipose tissue mRNA expression of both pro-inflammatory cytokines, but especially of IL-6 decreased dramatically after extensive weight loss whereas expression of adiponectin and its receptors increased. Weight loss also led to a significant reduction in liver IL-6 expression, whereas liver TNFα mRNA expression did not change. IL-6 and C-reactive protein serum levels decreased after weight loss whereas TNFα serum levels were below the detection limit before and after surgery. These effects were paralleled by reduced hepatic SOCS3 expression and improved insulin resistance 6 months after LAGB surgery. Conclusion Expression of IL-6 and TNFα mRNA is more pronounced in adipose compared to liver tissue in patients with severe obesity. Our results highlight excessive weight loss as a successful anti-inflammatory strategy.
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effects of weight loss induced by bariatric surgery on hepatic Adipocytokine expression
Journal of Hepatology, 2009Co-Authors: Alexander R Moschen, Clemens Molnar, Anna Maria Wolf, Helmut Weiss, Ivo Graziadei, Susanne Kaser, Christoph Ebenbichler, Sylvia Stadlmann, Patrizia Moser, Herbert TilgAbstract:Background/Aims Adipocytokines play a key role in the pathophysiology of non-alcoholic fatty liver diseases (NAFLD). Whereas adiponectin has mainly anti-inflammatory functions, leptin, resistin and pre-B cell enhancing factor (PBEF)/Nampt/visfatin are considered as mainly pro-inflammatory mediators regulating metabolic and immune processes. Methods We prospectively examined the effect of weight loss on systemic levels and/or hepatic expression of adiponectin/adiponectin receptors, leptin/leptin receptors, resistin and PBEF/Nampt/visfatin. Severely obese patients underwent laparoscopic adjustable gastric banding (LABG) and serum samples ( n =30) were collected before, and after 6 and 12 months. Paired liver biopsies (before and 6 months after LABG) were obtained from 18 patients. Results Bariatric surgery improved insulin resistance, abnormal liver function tests and liver histology. Pronounced weight loss after 6 and 12 months was accompanied by a significant increase in serum adiponectin levels whereas both leptin and PBEF/Nampt/visfatin levels decreased. Resistin serum levels increased after 6 months but fell below baseline values after 12 months. Liver mRNA expression of adiponectin increased slightly after 6 months whereas leptin mRNA expression did not change. Interestingly, weight loss resulted in a significant decrease of hepatic mRNA expression of resistin, PBEF/Nampt/visfatin and both leptin receptor isoforms while expression of type 1 and 2 adiponectin receptor was not affected. Liver immunohistochemistry performed on index and follow-up liver biopsies revealed an increase in adiponectin staining, showed no effect on resistin/leptin positivity, and demonstrated a decrease in PBEF/Nampt/visfatin immunoreactivity. Conclusions Weight loss after LABG surgery drives the Adipocytokine milieu towards a more anti-inflammatory direction both systemically and in the liver.
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visfatin an Adipocytokine with proinflammatory and immunomodulating properties
Journal of Immunology, 2007Co-Authors: Alexander R Moschen, Arthur Kaser, Barbara Enrich, Birgit A Mosheimer, Milan Theurl, Harald Niederegger, Herbert TilgAbstract:Adipocytokines are mainly adipocyte-derived cytokines regulating metabolism and as such are key regulators of insulin resistance. Some Adipocytokines such as adiponectin and leptin affect immune and inflammatory functions. Visfatin (pre-B cell colony-enhancing factor) has recently been identified as a new Adipocytokine affecting insulin resistance by binding to the insulin receptor. In this study, we show that recombinant visfatin activates human leukocytes and induces cytokine production. In CD14(+) monocytes, visfatin induces the production of IL-1beta, TNF-alpha, and especially IL-6. Moreover, it increases the surface expression of costimulatory molecules CD54, CD40, and CD80. Visfatin-stimulated monocytes show augmented FITC-dextran uptake and an enhanced capacity to induce alloproliferative responses in human lymphocytes. Visfatin-induced effects involve p38 as well as MEK1 pathways as determined by inhibition with MAPK inhibitors and we observed activation of NF-kappaB. In vivo, visfatin induces circulating IL-6 in BALB/c mice. In patients with inflammatory bowel disease, plasma levels of visfatin are elevated and its mRNA expression is significantly increased in colonic tissue of Crohn's and ulcerative colitis patients compared with healthy controls. Macrophages, dendritic cells, and colonic epithelial cells might be additional sources of visfatin as determined by confocal microscopy. Visfatin can be considered a new proinflammatory Adipocytokine.
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Adipocytokines mediators linking adipose tissue inflammation and immunity
Nature Reviews Immunology, 2006Co-Authors: Herbert Tilg, Alexander R MoschenAbstract:Adipose tissue produces several inflammatory mediators, including the Adipocytokines adiponectin, leptin and resistin. Here, recent advances in our understanding of the role of these Adipocytokines in inflammation and immunity are discussed, highlighting the importance of these mediators in obesity-associated diseases. There has been much effort recently to define the role of Adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The Adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several Adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other Adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.
Alexander R Moschen - One of the best experts on this subject based on the ideXlab platform.
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adiponectin key player in the adipose tissue liver crosstalk
Current Medicinal Chemistry, 2012Co-Authors: Alexander R Moschen, V Wieser, Herbert TilgAbstract:The adipose tissue has recently emerged as an important endocrine organ releasing numerous mediators including Adipocytokines, classical cytokines and others. Adiponectin, one of the major products of adipocytes, is a prototypic anti-diabetic Adipocytokine, the actions of which are mainly exerted by the activation of AMP-activated kinase and peroxisome proliferator-activated receptor alpha. This Adipocytokine is one of the most abundant circulating (adipo)cytokines in health. Non-alcoholic fatty liver disease (NAFLD), the major reason for abnormal liver functions in the western world, is commonly associated with obesity, insulin resistance and decreased adiponectin serum levels. Adiponectin has many anti-inflammatory activities and suppresses tumour necrosis factor-alpha (TNF), a cytokine of key importance in NAFLD. The anti-inflammatory effects of adiponectin are also exerted by induction of the anti-inflammatory cytokines interleukin-10 (IL-10) or IL-1 receptor antagonist and up-regulation of heme-oxygenase-1. Whereas the liver probably is not a relevant source of circulating adiponectin, it is a major target organ for many adiponectin effects. Adiponectin is able to regulate steatosis, insulin resistance, inflammation and fibrosis. NAFLD is also associated with decreased liver expression of the two adiponectin receptors (AdipoR1 and 2) thereby contributing to a state of hepatic adiponectin resistance. In contrast, most other liver diseases especially in advanced disease states exhibit increased adiponectin serum levels with highest levels observed in cirrhosis. Targeting adiponectin could evolve as a major treatment concept especially for fatty liver diseases in the future.
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anti inflammatory effects of excessive weight loss potent suppression of adipose interleukin 6 and tumour necrosis factor α expression
Gut, 2010Co-Authors: Alexander R Moschen, Arthur Kaser, Clemens Molnar, Helmut Weiss, Ivo Graziadei, Susanne Kaser, Christoph Ebenbichler, Sabine Geiger, Herbert TilgAbstract:Objective Severe obesity is a chronic inflammatory disease where various cytokines/Adipocytokines play a key role. Pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumour necrosis factor-α (TNFα) are produced by human adipose tissue dependent on the degree of obesity. Mouse studies suggest a key role of adipose tissue-derived IL-6 in hepatic insulin resistance via modification of liver suppressor of cytokine signalling 3 (SOCS-3) expression. Design and methods We examined the effect of excessive weight loss on systemic levels, subcutaneous and visceral adipose tissue and liver expression of IL-6 and TNFα in 20 severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB). Furthermore, we studied liver expression of SOCS3, an important regulator of insulin resistance, and fat tissue expression of the anti-inflammatory Adipocytokine adiponectin and its receptors. Serum and tissue samples were collected before and 6 months after LAGB surgery. Results IL-6/TNFα mRNA expression before weight loss were similar in subcutaneous and visceral adipose tissue and much higher compared to hepatic expression. Subcutaneous adipose tissue mRNA expression of both pro-inflammatory cytokines, but especially of IL-6 decreased dramatically after extensive weight loss whereas expression of adiponectin and its receptors increased. Weight loss also led to a significant reduction in liver IL-6 expression, whereas liver TNFα mRNA expression did not change. IL-6 and C-reactive protein serum levels decreased after weight loss whereas TNFα serum levels were below the detection limit before and after surgery. These effects were paralleled by reduced hepatic SOCS3 expression and improved insulin resistance 6 months after LAGB surgery. Conclusion Expression of IL-6 and TNFα mRNA is more pronounced in adipose compared to liver tissue in patients with severe obesity. Our results highlight excessive weight loss as a successful anti-inflammatory strategy.
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effects of weight loss induced by bariatric surgery on hepatic Adipocytokine expression
Journal of Hepatology, 2009Co-Authors: Alexander R Moschen, Clemens Molnar, Anna Maria Wolf, Helmut Weiss, Ivo Graziadei, Susanne Kaser, Christoph Ebenbichler, Sylvia Stadlmann, Patrizia Moser, Herbert TilgAbstract:Background/Aims Adipocytokines play a key role in the pathophysiology of non-alcoholic fatty liver diseases (NAFLD). Whereas adiponectin has mainly anti-inflammatory functions, leptin, resistin and pre-B cell enhancing factor (PBEF)/Nampt/visfatin are considered as mainly pro-inflammatory mediators regulating metabolic and immune processes. Methods We prospectively examined the effect of weight loss on systemic levels and/or hepatic expression of adiponectin/adiponectin receptors, leptin/leptin receptors, resistin and PBEF/Nampt/visfatin. Severely obese patients underwent laparoscopic adjustable gastric banding (LABG) and serum samples ( n =30) were collected before, and after 6 and 12 months. Paired liver biopsies (before and 6 months after LABG) were obtained from 18 patients. Results Bariatric surgery improved insulin resistance, abnormal liver function tests and liver histology. Pronounced weight loss after 6 and 12 months was accompanied by a significant increase in serum adiponectin levels whereas both leptin and PBEF/Nampt/visfatin levels decreased. Resistin serum levels increased after 6 months but fell below baseline values after 12 months. Liver mRNA expression of adiponectin increased slightly after 6 months whereas leptin mRNA expression did not change. Interestingly, weight loss resulted in a significant decrease of hepatic mRNA expression of resistin, PBEF/Nampt/visfatin and both leptin receptor isoforms while expression of type 1 and 2 adiponectin receptor was not affected. Liver immunohistochemistry performed on index and follow-up liver biopsies revealed an increase in adiponectin staining, showed no effect on resistin/leptin positivity, and demonstrated a decrease in PBEF/Nampt/visfatin immunoreactivity. Conclusions Weight loss after LABG surgery drives the Adipocytokine milieu towards a more anti-inflammatory direction both systemically and in the liver.
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visfatin an Adipocytokine with proinflammatory and immunomodulating properties
Journal of Immunology, 2007Co-Authors: Alexander R Moschen, Arthur Kaser, Barbara Enrich, Birgit A Mosheimer, Milan Theurl, Harald Niederegger, Herbert TilgAbstract:Adipocytokines are mainly adipocyte-derived cytokines regulating metabolism and as such are key regulators of insulin resistance. Some Adipocytokines such as adiponectin and leptin affect immune and inflammatory functions. Visfatin (pre-B cell colony-enhancing factor) has recently been identified as a new Adipocytokine affecting insulin resistance by binding to the insulin receptor. In this study, we show that recombinant visfatin activates human leukocytes and induces cytokine production. In CD14(+) monocytes, visfatin induces the production of IL-1beta, TNF-alpha, and especially IL-6. Moreover, it increases the surface expression of costimulatory molecules CD54, CD40, and CD80. Visfatin-stimulated monocytes show augmented FITC-dextran uptake and an enhanced capacity to induce alloproliferative responses in human lymphocytes. Visfatin-induced effects involve p38 as well as MEK1 pathways as determined by inhibition with MAPK inhibitors and we observed activation of NF-kappaB. In vivo, visfatin induces circulating IL-6 in BALB/c mice. In patients with inflammatory bowel disease, plasma levels of visfatin are elevated and its mRNA expression is significantly increased in colonic tissue of Crohn's and ulcerative colitis patients compared with healthy controls. Macrophages, dendritic cells, and colonic epithelial cells might be additional sources of visfatin as determined by confocal microscopy. Visfatin can be considered a new proinflammatory Adipocytokine.
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Adipocytokines mediators linking adipose tissue inflammation and immunity
Nature Reviews Immunology, 2006Co-Authors: Herbert Tilg, Alexander R MoschenAbstract:Adipose tissue produces several inflammatory mediators, including the Adipocytokines adiponectin, leptin and resistin. Here, recent advances in our understanding of the role of these Adipocytokines in inflammation and immunity are discussed, highlighting the importance of these mediators in obesity-associated diseases. There has been much effort recently to define the role of Adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The Adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several Adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other Adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.
Yuji Matsuzawa - One of the best experts on this subject based on the ideXlab platform.
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adiponectin a key player in obesity related disorders
Current Pharmaceutical Design, 2010Co-Authors: Yuji MatsuzawaAbstract:Recent studies revealed that adipose tissue is not only an energy storing organ, but is a kind of endocrine organ which secretes a variety of bioactive substances, so-called adipokines or Adipocytokines. Visceral fat accumulation is associated with hypersecretion of Adipocytokines such as tumor necrosis factor-alpha and plasminogen activator inhibitor-1 which may regulate inflammatory and atherogenic diseases. Adiponectin is a relatively new Adipocytokine which we discovered in 1996 and has anti-diabetic, anti-atherogenic and anti-inflammatory properties. Adiponectin is present in plasma at a very high concentration, but in contrast to other Adipocytokines, its production is reduced in subjects with visceral fat accumulation and the plasma levels are negatively correlated with visceral adiposity. Hypoadiponectinemia induced by visceral fat accumulation is closely associated with type 2 diabetes, lipid disorders, hypertension and also certain inflammatory diseases. In this review, the mechanisms of obesity-related diseases including nonalcoholic fatty liver disease will be discussed from the aspect of important roles of Adipocytokines, especially adiponectin.
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adiponectin a key Adipocytokine in metabolic syndrome
Clinical Science, 2006Co-Authors: Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Yoshihisa Okamoto, Peter LibbyAbstract:The metabolic syndrome, a cluster of metabolic disorders often associated with visceral obesity, increases cardiovascular mortality and morbidity. As the body's largest endocrine organ, adipose tissue not only stores excess body energy, but also secretes a variety of bioactive Adipocytokines. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific Adipocytokine. Although the association of adiponectin with several diseases remains controversial, many clinical studies have demonstrated that low plasma concentrations of adiponectin (hypoadiponectinaemia) associate closely with obesity-related diseases, including atherosclerotic cardiovascular diseases, Type II diabetes mellitus, hypertension and dyslipidaemia. Accumulating experimental evidence indicates that adiponectin possesses anti-atherogenic, anti-inflammatory and anti-diabetic properties and may also participate importantly in the mechanism of metabolic syndrome and other diseases. Despite these associations, further clinical and experimental investigations will be needed to illuminate the in vivo pathophysiological significance of this protein. Although evaluation of adiponectin as a novel therapy will ultimately require clinical intervention studies, this mediator may represent a novel target for the prevention and treatment of visceral obesity metabolic syndrome.
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therapy insight Adipocytokines in metabolic syndrome and related cardiovascular disease
Nature Reviews Cardiology, 2006Co-Authors: Yuji MatsuzawaAbstract:Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed Adipocytokines. Among Adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these Adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of Adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of Adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases.
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adiponectin and metabolic syndrome
Arteriosclerosis Thrombosis and Vascular Biology, 2004Co-Authors: Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Iichiro ShimomuraAbstract:In this review article, the crucial roles of adipocytes in the development of so-called metabolic syndrome and vascular disease are reviewed, focusing on adipocyte-derived bioactive substances, Adipocytokines. Recent progress in adipocyte biology shows that adipocytes are not merely energy-storing cells but that they secrete a variety of hormones cytokines, growth factors, and other bioactive substances. To search for novel Adipocytokines by the large-scale random sequence analysis of expressed genes in adipocytes, we identified an adipose-specific collagen-like molecule, adiponectin. This novel Adipocytokine has plural biofunctions, such as antidiabetic, antiatherosclerotic, and antiinflammatory functions. Adiponectin plasma levels decrease with the accumulation of visceral adipose tissue. In this review, we discuss the link of adiponectin to visceral adiposity, insulin resistance, and vascular diseases.
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obesity adiponectin and vascular inflammatory disease
Current Opinion in Lipidology, 2003Co-Authors: Noriyuki Ouchi, Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Kenneth WalshAbstract:Purpose of review Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as Adipocytokines, and that dysregulation of Adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic Adipocytokine, and vascular inflammation. Recent findings Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. Summary Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease.
Shinji Kihara - One of the best experts on this subject based on the ideXlab platform.
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blockade of angiotensin ii type 1 receptor reduces oxidative stress in adipose tissue and ameliorates Adipocytokine dysregulation
Kidney International, 2006Co-Authors: Akifumi Kurata, Hitoshi Nishizawa, Shinji Kihara, Norikazu Maeda, Mina Sonoda, Takuya Okada, Koji Ohashi, Toshiyuki Hibuse, Koichi Fujita, Atsutaka YasuiAbstract:Dysregulated production of Adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease (CKD) associated with metabolic syndrome. The aim of this study was to determine the effects of treatment with angiotensin II (Ang II) type-1 receptor blocker (ARB) on the regulation of Adipocytokines. Olmesartan, an ARB, significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice, without affecting body weight, but had no effect on plasma adiponectin levels in lean mice. Olmesartan also ameliorated dysregulation of Adipocytokines in obesity, such as tumor necrosis factor-α, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, and serum amyloid A3. Olmesartan significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue. In cultured adipocytes, olmesartan acted as an antioxidant and improved Adipocytokine dysregulation. Our results indicate that blockade of Ang II receptor ameliorates Adipocytokine dysregulation and that such action is mediated, at least in part, by targeting oxidative stress in obese adipose tissue. Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD.
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adiponectin a key Adipocytokine in metabolic syndrome
Clinical Science, 2006Co-Authors: Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Yoshihisa Okamoto, Peter LibbyAbstract:The metabolic syndrome, a cluster of metabolic disorders often associated with visceral obesity, increases cardiovascular mortality and morbidity. As the body's largest endocrine organ, adipose tissue not only stores excess body energy, but also secretes a variety of bioactive Adipocytokines. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific Adipocytokine. Although the association of adiponectin with several diseases remains controversial, many clinical studies have demonstrated that low plasma concentrations of adiponectin (hypoadiponectinaemia) associate closely with obesity-related diseases, including atherosclerotic cardiovascular diseases, Type II diabetes mellitus, hypertension and dyslipidaemia. Accumulating experimental evidence indicates that adiponectin possesses anti-atherogenic, anti-inflammatory and anti-diabetic properties and may also participate importantly in the mechanism of metabolic syndrome and other diseases. Despite these associations, further clinical and experimental investigations will be needed to illuminate the in vivo pathophysiological significance of this protein. Although evaluation of adiponectin as a novel therapy will ultimately require clinical intervention studies, this mediator may represent a novel target for the prevention and treatment of visceral obesity metabolic syndrome.
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adiponectin and metabolic syndrome
Arteriosclerosis Thrombosis and Vascular Biology, 2004Co-Authors: Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Iichiro ShimomuraAbstract:In this review article, the crucial roles of adipocytes in the development of so-called metabolic syndrome and vascular disease are reviewed, focusing on adipocyte-derived bioactive substances, Adipocytokines. Recent progress in adipocyte biology shows that adipocytes are not merely energy-storing cells but that they secrete a variety of hormones cytokines, growth factors, and other bioactive substances. To search for novel Adipocytokines by the large-scale random sequence analysis of expressed genes in adipocytes, we identified an adipose-specific collagen-like molecule, adiponectin. This novel Adipocytokine has plural biofunctions, such as antidiabetic, antiatherosclerotic, and antiinflammatory functions. Adiponectin plasma levels decrease with the accumulation of visceral adipose tissue. In this review, we discuss the link of adiponectin to visceral adiposity, insulin resistance, and vascular diseases.
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obesity adiponectin and vascular inflammatory disease
Current Opinion in Lipidology, 2003Co-Authors: Noriyuki Ouchi, Yuji Matsuzawa, Shinji Kihara, Tohru Funahashi, Kenneth WalshAbstract:Purpose of review Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as Adipocytokines, and that dysregulation of Adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic Adipocytokine, and vascular inflammation. Recent findings Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. Summary Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease.
Morihiro Matsuda - One of the best experts on this subject based on the ideXlab platform.
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nitric oxide dysregulates Adipocytokine expression in 3t3 l1 adipocytes
Biochemical and Biophysical Research Communications, 2007Co-Authors: Maiko Nozaki, Naomi Hosogai, Katsumori Segawa, Atsunori Fukuhara, Morihiro Matsuda, Ryutaro Komuro, Yosuke Okuno, Manabu Abe, Iichiro ShimomuraAbstract:Abstract Obesity is associated with infiltration of macrophages into adipose tissue, and macrophages are an important source of nitric oxide (NO). Dysregulated production of fat-derived secretory factor, Adipocytokine, leads to obesity-linked metabolic disorders. However, it has not been fully determined whether NO might have direct effects on Adipocytokine expressions. Here, we show that NO donor treatment downregulated gene expression and secretion of adiponectin, and upregulated mRNA levels of PAI-1 and IL-6. NO donor reduced promoter activity of adiponectin through PPARγ responsive element. Moreover, NO donor activated JNK and NF-κB pathways, and inhibitors of these pathways rescued NO-mediated upregulation of PAI-1 and IL-6. Analysis of adipose tissue of high-fat-fed obese mice showed upregulation of PAI-1 and IL-6 expression, increased synthesis of NO, and downregulation of adiponectin. Our results suggest that increased NO synthesis might be partly responsible for dysregulation of Adipocytokines in adipose tissue.
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Adipose tissue hypoxia in obesity and its impact on Adipocytokine dysregulation
Diabetes, 2007Co-Authors: Naomi Hosogai, Yugo Miyata, Shigetada Furukawa, Katsumori Segawa, Sachiyo Tanaka, Kazuya Oshima, Atsunori Fukuhara, Yoshihiro Tochino, Ryutaro Komuro, Morihiro MatsudaAbstract:Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, Adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to Adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of Adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of Adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of Adipocytokines and metabolic syndrome in obesity.
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visfatin a protein secreted by visceral fat that mimics the effects of insulin
Science, 2005Co-Authors: Atsunori Fukuhara, Katsumori Segawa, Morihiro Matsuda, Masako Nishizawa, Masaki Tanaka, Kae Kishimoto, Yasushi Matsuki, Mirei Murakami, Tomoko Ichisaka, Hiroko MurakamiAbstract:Fat tissue produces a variety of secreted proteins (Adipocytokines) with important roles in metabolism. We isolated a newly identified Adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher levels of plasma glucose relative to wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/or new therapies for metabolic disorders such as diabetes.