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

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.
 ...
PMID:Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha. 1597 14

Fatty acids and their metabolites regulate gene expression and immunological pathways. Furthermore, obese individuals frequently have increased circulating fatty acid concentrations, and localized inflammation in adipose tissue may facilitate the systemic inflammation associated with the insulin resistance of obesity. Although palmitate induces inflammation (i.e., activates proinflammatory pathways) in myotubes, the effects of fatty acids on inflammatory processes in adipocytes have not been established. Therefore, we examined the potential for palmitate, laurate, and docosahexaenoic acid (DHA) to modulate inflammation in 3T3-L1 adipocytes. Palmitate, but not DHA or laurate, induced nuclear factor kappaB (NF-kappaB)-driven luciferase activity and interleukin-6 (IL-6) expression (P < 0.05). Inhibition of fatty acyl Co-A synthase (FACS) with triacsin C suppressed palmitate-induced NF-kappaB activation (P < 0.05), but caused an additive increase in palmitate-induced IL-6 expression (P < 0.05). Disrupting mitogen-activated protein kinase/Erk kinase (MEK) and protein kinase C (PKC) activity with U0126 and Bisindolylmaleimide (Bis), respectively, suppressed palmitate-induced IL-6 expression (P < 0.05), but had no effect on NF-kappaB reporter gene activity (P > 0.05). However, the phosphoinositide-3 kinase (PI3K) inhibitor, wortmannin, alone and additively with palmitate, activated the NF-kappaB reporter gene and induced IL-6 expression (P < 0.05). Palmitate also induced the mRNA expression of tumor necrosis factor alpha (TNFalpha) (P < 0.05), but the increase in mRNA abundance was not reflected in a greater protein concentration in the media (P > 0.05). These data indicate that palmitate induces inflammation in adipocytes, and that this is not a generalized effect of all SFA. Furthermore, PI3K may act constitutively to suppress inflammation. Consequently, inhibition of this enzyme may promote and exacerbate the inflammation in adipose tissue that is associated with obesity and insulin resistance.
 ...
PMID:Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. 1604 6

Medroxyprogesterone acetate (MPA), a widely used synthetic progestational contraceptive, occasionally leads to Cushingoid side effects such as hypertension, fluid retention, and centripetal obesity. We investigated the effect of MPA on classic mineralocorticoid target genes, alpha-epithelial Na channel (ENaC) and sgk1, in the collecting duct. In adrenalectomized mice, aldosterone, dexamethasone, and MPA increased alpha-ENaC mRNA levels in kidney cortex. MPA and dexamethasone, but not progesterone, dose dependently increased alpha-ENaC and sgk1 mRNA in M-1 and in Madin-Darby canine kidney-C7 cells, both collecting duct cell lines. The stimulatory effect of MPA and dexamethasone on alpha-ENaC expression was inhibited by RU-38486, a combined glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, but not by Org31710, a pure PR antagonist. MPA and dexamethasone dose dependently increased alpha-ENaC promoter-driven luciferase activity in M-1 cells, which was not inhibited by Org31710, indicating that MPA regulates alpha-ENaC in a PR-independent manner. When tested in HT29 cells, MPA could only stimulate alpha-ENaC-driven reporter activity when GR was coexpressed, confirming the requirement for functional GR in the transcriptional effect of MPA. The activation of steroid receptors such as GR can explain the apparent glucocorticoid effects of MPA, independent of PR activation.
 ...
PMID:Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia. 1618 95

Valproic acid (VPA) has been used for the treatment of epilepsy and bipolar disorders for more than 30 yr. Obesity and insulin resistance are common side effects of VPA treatment. Adiponectin is an adipocyte-derived protein that plays an important role in controlling insulin sensitivity and glucose homeostasis. In this report, we examined the effects of VPA on adiponectin gene expression in C57BL/6J mice and in differentiated 3T3-L1 adipocytes. VPA treatment significantly decreased adiponectin protein and mRNA levels in both mice and 3T3-L1 adipocytes. The adipocyte study showed that VPA inhibited adiponectin gene expression in a dose- and time-dependent manner. Repression of adiponectin expression by VPA occurred at the transcription level and correlated with inhibition of histone deacetylase activity. Therapeutic concentrations of VPA increased overall histone acetylation and increased adiponectin promoter-driven luciferase expression in fibroblasts, but decreased adiponectin promoter activity in differentiated 3T3-L1 adipocytes. VPA treatment decreased adipogenic transcription factor CCAAT/enhancer binding protein-alpha (C/EBPalpha) levels and binding of C/EBPalpha to the adiponectin promoter without altering the levels of peroxisome proliferator-activated receptor-gamma and steroid regulatory element binding protein-1. Furthermore, VPA did not suppress adiponectin gene expression in C/EBPalpha gene-deficient adipocytes that stably expressed exogenous peroxisome proliferator-activated receptor-gamma2. Together, these results demonstrate that histone deacetylase inhibitor VPA suppresses adiponectin gene expression in mature adipocytes. The study also provides evidence that diminished C/EBPalpha protein level and decreased binding at the adiponectin promoter mediate the inhibitory effects of VPA on adiponectin gene transcription.
 ...
PMID:Suppression of adiponectin gene expression by histone deacetylase inhibitor valproic acid. 1628 59

We have screened 356 libraries of Korean herbal plant extracts to find potential anti-obesity drugs. We employed the recently developed fluorescence polarization high throughput screening (FP HTS) assays of human neuropeptide FF (NPFF) receptors in 384-well microtiter plates. The primary hits were cherry-picked from the libraries and further analyzed by secondary displacement curve assays, in vitro GTPgammaS binding assays and cell-based CRE luciferase reporter assays. Agonists of NPFF receptors showed biphasic affinity curves while the antagonist, BIBP 3226, gave a monophasic affinity curve in competitive binding assays. We isolated and characterized two agonists of human NPFF2 receptor, PC 314 with K(i) of 1.42 microM, and PC 315 with K(i) of 2.17 microM from Schizandra chinensis. PC 314 and PC 315 have been characterized as benzoylgomisin Q (M.W. 552) and gomisin G (M.W. 536). We report that PC 314 and PC 315 are the first non-peptide, natural compounds, which bind to human NPFF2 receptors with good affinity. PC 314 and PC 315 inhibit forskolin-stimulated luciferase expression when CHO cells are co-transfected with NPFF2 receptor and CRE reporter vector. They possess the pharmacological and functional profiles of full agonists. The FP HTS system provides a specific, sensitive and reproducible methodology for studying and screening NPFF receptor ligands.
 ...
PMID:The high throughput screening of neuropeptide FF2 receptor ligands from Korean herbal plant extracts. 1648 13

Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis.
 ...
PMID:Severe pulmonary metastasis in obese and diabetic mice. 1699 95

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.
 ...
PMID:Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE. 1707 69

Previous epidemiologic studies have suggested that periodontal disease is closely related to obesity and glucose tolerance. As the level of adiponectin, an adipocyte-derived cytokine, in plasma had been reported to decrease in obese and type 2 diabetes patients, we explored the role of adiponectin in the etiology of periodontitis using the D clone of RAW264, a clone that exhibits highly efficient osteoclast formation, to determine whether adiponectin acts as a regulatory molecule in osteoclast formation stimulated by lipopolysaccharide of periodontopathic bacteria. We observed that adiponectin acted as a potent inhibitor of osteoclast formation stimulated by Toll-like receptor 4 (TLR4) ligand and receptor activator of NF-kappaB ligand (RANKL). Because NF-kappaB is an important transcription factor in osteoclast formation, we examined the effect of adiponectin on its transcriptional activity. A luciferase assay showed that adiponectin was able to inhibit the TLR4-mediated NF-kappaB activity in RAW264 cells. In addition, we observed that the cytokine was actually able to inhibit TLR4-mediated expression of the gene for inducible nitric oxide synthase and production of nitric oxide in the cells. These observations strongly suggest that adiponectin may function as a negative regulator of lipopolysaccharide/RANKL-mediated osteoclast formation in periodontal disease.
 ...
PMID:Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans. 1709 90

Although resistin was first suggested as a possible link between obesity and diabetes, we have demonstrated previously that expression of resistin is induced by LPS (lipopolysaccharide). In the present study, we showed that LPS increased levels of resistin mRNA and promoter activity in murine RAW264.7 macrophages. Investigation of cis-regulatory elements in the mouse resistin promoter required for LPS-mediated induction showed that an Octamer (ATTTGCAT) element, located at -914 to -907, was required for maximal promoter activity in response to LPS stimulation. Co-transfection of RAW264.7 cells with a resistin promoter-luciferase construct and an Oct-1 or Oct-2 expression plasmid (pCG-Oct-1 or pCG-Oct-2) showed that Oct-2, but not Oct-1, activated the resistin promoter upon LPS treatment. Binding of Oct-2 to the Octamer element was demonstrated by supershift DNA-affinity precipitation and chromatin immunoprecipitation assays. Reverse transcription-PCR and Western blot results showed that levels of Oct-2 mRNA and protein were both up-regulated by LPS in RAW264.7 cells. The LPS-induced increase in Oct-2 protein was inhibited by LY294002 (a phosphoinositide 3-kinase inhibitor) post-transcriptionally, and the inhibition also resulted in a lower response of both resistin mRNA and promoter activity to LPS treatment. Moreover, specific knockdown of Oct-2 by RNA interference impaired the LPS-induced increase in resistin mRNA and promoter activity. Together, these results indicate that Oct-2 is involved in the LPS-mediated induction of resistin gene expression in macrophages and suggest that activation of Oct-2 is a part of LPS signalling pathways in macrophages.
 ...
PMID:A novel role for Oct-2 in the lipopolysaccharide-mediated induction of resistin gene expression in RAW264.7 cells. 1710 42

Diabetes mellitus is frequently associated with coagulation disorders such as coronary heart disease and stroke. We aimed to clarify the molecular mechanism whereby hyperglycemia causes the procoagulant state. HuH7 human hepatocyte cells were treated with high glucose alone or in combination with proinflammatory cytokines, and the effects on the activity of the transcription factor nuclear factor kappa-B (NF-kappaB), which mediates the expression of acute-phase and coagulation-related genes, were examined. The results showed that increasing the medium glucose concentration from 3 to 24 mM significantly enhanced NF-kappaB-luciferase activity by 40% in the presence of insulin. The effect was promoter specific and not mimicked by comparable hyperosmolality with L-glucose. Proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) also stimulated NF-kappaB-dependent transcription and showed an additive effect with high glucose. Similar effects were obtained on acute-phase or coagulation/fibrinolysis-related gene promoters such as fibrinogen or plasminogen activator inhibitor-1, all of which are shown to have NF-kappaB-mediated transcription. Finally, pretreatment of the cells with an antioxidant PDTC completely abolished the effect of high glucose and markedly attenuated that of TNF-alpha, suggesting the involvement of reactive oxygen species. These results suggest that (1) high glucose as well as proinflammatory cytokines have positive effects on NF-kappaB-mediated transcription in an additive manner and enhance coagulation-related gene expression and (2) the effects are mediated, at least partly, by the generation of oxidative stress and may be responsible for the high prevalence of thrombotic disorders in the metabolic syndrome with diabetes, hyperinsulinemia, obesity, and/or inflammation.
 ...
PMID:High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro. 1718 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>