Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.
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PMID:Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? 1020 82

We reported previously that genistein enhances the expression of genes involved in fatty acid catabolism through activation of peroxisome proliferator-activated receptor (PPAR) alpha in HepG2 cells, suggesting that genistein holds great promise for therapeutic applications to lipid abnormalities such as obesity and hyperlipidemia in humans. In this study, we examined the changes in hepatic transcriptional profiles using cDNA microarrays in mice with high-fat diet (HFD)-induced obesity supplemented with genistein. C57BL/6J male mice (n = 10/group) were fed a low-fat diet (LFD), a HFD, or a HFD supplemented with 2 g/kg genistein (HFD+GEN) for 12 wk. Mice fed the HFD had abnormal lipid profiles and significantly greater body weight and visceral fat accumulation than the LFD-fed group. Genistein supplementation improved lipid profiles and hepatic steatosis and attenuated the increases in body weight and visceral fat in HFD-fed mice. The cDNA microarrays revealed marked alterations in the expression of 107 genes in the mice fed the HFD and/or the HFD+GEN. Of 97 transcripts altered in the HFD-fed group, 84 genes were normalized by genistein supplementation. However, several genes involved in fatty acid catabolism were not normalized but were still upregulated in the HFD+GEN-fed group, relative to the LFD-fed group. Furthermore, carnitine O-octanoyltransferase, which accelerates fatty acid oxidation, was not affected by the HFD, but was induced by genistein supplementation. These results are consistent with our previous study showing that genistein is an activator of PPAR alpha in vitro. This study showed beneficial effects of genistein supplementation in preventing the development of obesity and metabolic abnormalities in mice with diet-induced obesity. Our results also provide interesting information about the genes associated with the beneficial effects of genistein as well as the mechanisms underlying the development and maintenance of the obesity phenotype in vivo.
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PMID:Hepatic gene expression profiles are altered by genistein supplementation in mice with diet-induced obesity. 1562 29

Phytochemicals such as soy isoflavone genistein have been reported to possess therapeutic effects for obesity, diabetes, and cardiovascular diseases. In the present study, the molecular basis of selective phytochemicals with emphasis on their ability to control intracellular signaling cascades of AMP-activated kinase (AMPK) responsible for the inhibition of adipogenesis was investigated. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, emerges as a possible target molecule of anti-obesity. Hypothalamic AMPK was found to integrate nutritional and hormonal signals modulating feeding behavior and energy expenditure. We have investigated the effects of genistein, EGCG, and capsaicin on adipocyte differentiation in relation to AMPK activation in 3T3-L1 cells. Genistein (20-200muM) significantly inhibited the process of adipocyte differentiation and led to apoptosis of mature adipocytes. Genistein, EGCG, and capsaicin stimulated the intracellular ROS release, which activated AMPK rapidly. We suggest that AMPK is a novel and critical component of both inhibition of adipocyte differentiation and apoptosis of mature adipocytes by genistein or EGCG or capsaicin further implying AMPK as a prime target of obesity control.
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PMID:Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. 1623 47

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.
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PMID:Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. 2162 20

The soy isoflavone genistein targets adipose tissue and elicits physiological effects that may vary based on dietary intake. We hypothesized that the adipose effects of genistein are dose and gender dependent. Four-week-old C57BL/6 male and female mice received daily oral doses of genistein (50-200,000 microg/kg.d) or 17beta-estradiol (E2) (5 microg/kg.d) for 15 d or a diet containing 800 ppm genistein. Genistein increased epididymal and renal fat pad and adipocyte size at doses up to 50,000 microg/kg.d or at 800 ppm in the diet in males but not in females. The alteration in adipocity correlated with changes in peripheral insulin resistance. These treatments increased genistein serum concentrations from 35+/-6 to 103+/-26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 microg/kg.d genistein dose decreased adipose tissue weight similarly to E2. This genistein dose down-regulated estrogen receptor (beta more than alpha) and progesterone receptor expression and induced estrogen-dependent adipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tK-LUC mice, which was positively modulated in other tissues (e.g. the lung). E2 down-regulated almost all examined adipogenic factors. Gene microarray analysis identified factors in fat metabolism and obesity-related phenotypes differentially regulated by low and high doses of genistein, uncovering its adipogenic and antiadipogenic actions. The lower dose induced the phospholipase A2 group 7 and the phospholipid transfer protein genes; the 200,000 microg/kg.d dose inhibited them. The antiadipogenic action of genistein and down-regulation of adipogenic genes required the expression of ERbeta. In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition.
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PMID:Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. 1695 45

Recent observations have highlighted adipogenesis alterations under exposure to several xenoestrogens at critical stages, and pointed at their possible involvement in the pathogenesis of obesity. However, it remains unclear whether these effects are mediated by classical estrogen receptor (ER) binding and subsequent transcriptional modulation. The aim of this study was to determine the (anti-)adipogenic impact of apigenin, bisphenol A, genistein and 17beta-estradiol at the onset of adipose cell maturation, and to correlate it to their estrogenic potential. In steroid-free conditions, 3T3-L1 preadipocytes were induced to differentiate in the presence of xenoestrogens for 2 days. DNA and triglyceride levels, leptin secretion and expression of Pref-1, C/EBPbeta, PPARgamma2, FAS, leptin and ERs were measured on days 0, 3 and 8 of differentiation. Genistein potently blocked mitotic clonal expansion and all markers of maturation. Bisphenol A and estradiol did not modify triglyceride accumulation but increased the expression of differentiation genes. Apigenin caused a weak but reversible delay in adipogenesis although it unexpectedly enhanced leptin synthesis. However, the expression of steroid hormone receptors was not associated with these differential effects. In conclusion, we could not put a clear estrogen-dependent mechanism forward, but early exposure to xenoestrogens persistently disrupted adipocyte gene expression and leptin synthesis.
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PMID:Dietary xenoestrogens differentially impair 3T3-L1 preadipocyte differentiation and persistently affect leptin synthesis. 1835 23

Genistein (G), an isoflavone, and guggulsterone (GS), the active substance in guggulipid, have been reported to possess therapeutic effects for obesity. In the present study, we investigated the effects of combinations of G plus GS on apoptosis and adipogenesis in 3T3-L1 cells. In mature adipocytes, G and GS individually caused apoptosis, but combination of G plus GS significantly increased apoptosis, more than either compound alone. Furthermore, G plus GS caused a greater increase in procaspase-3 cleavage, Bax expression, cytochrome c release, and proteolytic cleavage of PARP than either compound alone. In maturing preadipocytes G and GS each suppressed lipid accumulation, but the combination potentiated the inhibition of lipid accumulation. These results suggest that combination of genistein and guggulsterone may exert anti-obesity effects by inhibiting adipogenesis and inducing apoptosis in adipocytes.
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PMID:Enhanced pro-apoptotic and anti-adipogenic effects of genistein plus guggulsterone in 3T3-L1 adipocytes. 1852 10

Insulin resistance is a fundamental aspect for the etiology of non-insulin dependent diabetes mellitus (NIDDM) and has links with a wide array of secondary disorders including weight gain and obesity. The present study analyzes the effect of Cichorium intybus methanolic (CME) extract on glucose transport and adipocyte differentiation in 3T3-L1 cells by studying the radiolabelled glucose uptake and lipid accumulation assays, respectively. By performing detannification (CME/DT), the role of tannins present in CME on both the activities was evaluated. CME and CME/DT exhibited significant glucose uptake in 3T3-L1 adipocytes with a dose-dependent response. Glucose uptake profile in the presence of PI3K and IRTK inhibitors (Wortmannin and Genistein) substantiates the mechanism used by both the extracts. CME inhibited the differentiation of 3T3-L1 preadipocytes but failed to show glucose uptake in inhibitor treated cells. The activity exhibited by CME/DT is exactly vice versa to CME. Furthermore, the findings from PTP1B inhibition assay, mRNA and protein expression analysis revealed the unique behavior of CME and CME/DT. The duality exhibited by C. intybus through adipogenesis inhibition and PPARgamma up regulation is of interest. Current observation concludes that the activities possessed by C. intybus are highly desirable for the treatment of NIDDM because it reduces blood glucose levels without inducing adipogenesis in 3T3-L1 adipocytes.
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PMID:Tannins present in Cichorium intybus enhance glucose uptake and inhibit adipogenesis in 3T3-L1 adipocytes through PTP1B inhibition. 1853 69

Over the last decades, the prevalence of obesity and related diseases has increased rapidly in the Western world. Obesity is a disorder of energy balance and is associated with hyper-insulinemia, insulin resistance, and abnormalities in lipid metabolism, and it is one of the most important risk factors in the development of Type II diabetes, cardiovascular disease, atherosclerosis, and certain cancers. Because of the lower frequency of these diseases in Asian countries, attention has been turned toward the Asian diet, which consists highly of soy and soy-based products. The health benefits associated with soy consumption have been linked to the content of isoflavones, the main class of the phytoestrogens. As a result of their structural similarities to endogenous estrogens, isoflavones elicit weak estrogenic effects by competing with 17beta-estradiol (E2) for binding to the intranuclear estrogen receptors (ERs) and exert estrogenic or antiestrogenic effects in various tissues. The estrogenic activities of soy isoflavones are thought to play an important role in their health-enhancing properties. Additionally, the isoflavones have been proved to exert non-ER-mediated effects through numerous other pathways. Genistein, daidzein, and glycitein are the principal isoflavones in soy. Genistein is the most thoroughly examined of these, because it is the most prevalent isoflavone in soy and the most active of these compounds, because of its higher binding affinity for the ER. Genistein and daidzein can be obtained in high levels in humans under certain nutritional conditions, and epidemiologic and laboratory data suggest that these compounds could have health benefits in human obesity. This review will focus on the latest results of research on isoflavones and their effect on obesity in cell cultures, rodents, and humans.
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PMID:The effects of soy isoflavones on obesity. 1853 67

The amount of soy products consumed in Japan is much greater than that in Western countries. Recent evidence indicates that soy isoflavones play a beneficial role in obesity, cancer, osteoporosis, and cardiovascular disease. The soybean isoflavone genistein is present at high levels in soy products. Genistein is structurally similar to 17beta-estradiol (E2), and genistein has been suggested to be act as E2 or an antagonist against E2. Genistein suppresses antigen-specific immune response in vivo and lymphocyte proliferation response in vitro. However, genistein enhances the cytotoxic response mediated by NK and cytotoxic T cells and the cytokine production from T cells. Thus, the effect of genistein on immunity is immune cell-dependent. Due to its unique effect on immune function, genistein has been used for the treatment of the diseases in animal models and it has been found that genistein inhibits allergic inflammatory responses. In this review, we summarize current studies related to the effect of isoflavone genistein on the immune system.
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PMID:Soy isoflavones and immunity. 1879 28


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