Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Obesity is considered a risk factor for many cancers, including breast cancer. Our laboratory has previously shown that leptin is mitogenic in many cancer cell lines, including breast. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. In addition, SOCS-3 expression (a leptin inducible inhibitor of leptin signaling), plus MAPK and PI3K signaling, were examined to determine their role in leptin-induced cell proliferation. Breast cancer cell lines, ZR75-1 and HTB-26, were treated with 0, 4, 40 or 80 ng/ml of leptin. Multiplex RT-PCR was performed to determine relative mRNA expression levels of the human short (huOB-Ra) or long (huOB-Rb) leptin receptor isoforms, or SOCS-3. MAPK and PI3K signaling was analyzed by phosphorylation of ERK and Akt, respectively, via Western blotting. Cell proliferation and inhibitor studies were analyzed by MTT assay. HTB-26 and ZR75-1 both expressed huOB-Ra, huOB-Rb and SOCS-3 mRNA; however, mRNA expression levels generally remained unchanged over time with leptin treatment. MAPK and PI3K pathways were activated in the presence of leptin over time. MAPK and PI3K inhibitors significantly blocked leptin-induced proliferation. Higher levels of circulating leptin contribute to breast cancer proliferation by activation of the MAPK and PI3K signaling pathways involved in cell growth and survival. The mitogenic effects of leptin are not a consequence of altered leptin receptor or SOCS-3 mRNA expression.
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PMID:Leptin receptor expression and cell signaling in breast cancer. 1652 50

Protein tyrosine phosphatases have a central role in the maintenance of normal cellular functionality. For example, PTP1B has been implicated in insulin-resistance, obesity, and neoplasia. Mitogen-activated protein kinase phosphatase-1 (MKP-1 or DUSP1) dephosphorylates and inactivates mitogen-activated protein kinase (MAPK) substrates, such as p38, JNK, and Erk, and has been implicated in neoplasia. The lack of readily available selective small molecule inhibitors of MKP family members has severely limited interrogation of their biological role. Inspired by a previously identified inhibitor (NSC 357756) of MKP-3, we synthesized seven NSC 357756 congeners, which were evaluated for in vitro inhibition against several protein phosphatases. Remarkably, none displayed potent inhibition against MKP-3, including the desamino NSC 357756 analog NU-154. Interestingly, NU-154 inhibited human PTP1B in vitro with an IC(50) value of 24 +/- 1 microM and showed little inhibition against Cdc25B, MKP-1, and VHR phosphatases. NU-126 [2-((E)-2-(5-cyanobenzofuran-2-yl)vinyl)-1H-indole-6-carbonitrile] inhibited MKP-1 and VHR in vitro but was less active against human MKP-3, Cdc25B, and PTP1B. The inhibition of MKP-1 by NU-126 was independent of redox processes. The benzofuran substructure represents a new potential scaffold for further analog development and provides encouragement that more selective and potent inhibitors of MKP family members may be achievable.
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PMID:Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1. 1669 71

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.
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PMID:TNFalpha up-regulates apelin expression in human and mouse adipose tissue. 1672 81

Obesity is an important risk factor for esophageal adenocarcinoma (EAC), and elevated serum leptin is characteristic of obesity. We hypothesized that leptin may have biological effects in promoting esophageal adenocarcinoma and examined the effects of leptin on the OE33 Barrett's-derived EAC line. Proliferation was assessed by dimethylthiazoldiphenyltetra-zoliumbromide and 5-bromo-2'-deoxyuridine incorporation assays and apoptosis by ELISA of intracellular nucleosomes. Intracellular signaling was examined using specific pharmacological inhibitors and direct detection of phosphorylated active kinases. Expression of the long and short leptin receptors by OE33 cells was confirmed by RT-PCR, Western blotting and immunocytochemistry. Leptin stimulated OE33 cell proliferation in a dose-dependent manner and inhibited apoptosis. These effects were dependent on cyclooxygenase (COX)-2 and replicated by adding prostaglandin E2 (PGE2). The effects of PGE2 and leptin were abolished by the EP-4 antagonist AH23848. ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus tyrosine kinase (JAK)-2 were activated upstream of COX-2 induction, whereas the epidermal growth factor receptor and c-Jun NH2-terminal kinase (JNK) were downstream of COX-2. The activation of ERK and Akt but not p38 MAPK was JAK2 dependent. PGE2 stimulated phosphorylation of JNK in an EGF receptor-dependent manner, and activation of the epidermal growth factor receptor required protein kinase C, src, and matrix metalloproteinase activities. We conclude that leptin stimulates cell proliferation and inhibits apoptosis in OAC cells via ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and JAK2-dependent activation of COX-2 and PGE2 production. Subsequent PGE2-mediated transactivation of the epidermal growth factor receptor and JNK activation are essential to the leptin effects. These effects may contribute to the greatly increased risk of esophageal adenocarcinoma in obesity.
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PMID:Leptin stimulates proliferation and inhibits apoptosis in Barrett's esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. 1674 Sep 77

Leptin is a 16 kDa product of the obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of leptin and suggested that leptin may be a biological link between obesity and cardiovascular pathologies. Activation of the renin-angiotensin and endothelin systems is associated with development of cardiovascular diseases and plasma renin levels are elevated in obese individuals. We therefore determined possible interaction between these factors in mediating hypertrophy in cultured neonatal rat ventricular myocytes. Treatment for 24 h with leptin (3.1 nM), angiotensin II (100 nM) or endothelin-1 (ET-1, 10 nM) significantly increased cell area by 37%, 36% and 35%, respectively and significantly increased gene expression of myosin light chain-2 and alpha-skeletal actin as well as leucine incorporation. The hypertrophic effects of all three agents were prevented by leptin and a leptin triple mutant receptor antagonist whereas the AT(1) receptor blocker (Sar1-lle(8))-Ang II or the ET(A) receptor blocker BQ123 was ineffective against leptin-induced hypertrophy. Both angiotensin II and ET-1 significantly increased leptin levels in the culture medium by fivefold. Moreover, both angiotensin II and ET-1 increased the gene expression of the short form (OBRa) by 180% and long form (OBRb) of leptin receptors by 200%, and this increase was abolished by both leptin receptor and leptin antibodies and leptin triple mutant. Although both angiotensin II and ET-1 increased phosphorylation of MAPK (p38, ERK1/2 and JNK) and NF-kappaB, the ability of leptin blockade to attenuate the hypertrophic responses was generally dissociated from these effects suggesting an alternate, yet to be identified cellular pathway mediating this role of leptin. Our studies therefore suggest a novel autocrine function for leptin in mediating the hypertrophic effects of both angiotensin II and ET-1 in cardiac myocytes.
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PMID:An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. 1680 60

Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of nonadipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e.g. IL-6, TNF-alpha, and IL-1beta) and chemokines (e.g. IL-8, monocyte chemoattractant protein-1) occurred primarily in the nonadipocyte fraction of newly differentiated human adipocytes. Nonadipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 and adipocyte enhancer protein-1 and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from approximately 0-90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor-kappaB and MAPK signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with: 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor (PPAR)-gamma reporter construct and increased phosphorylation of PPARgamma, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces nuclear factor-kappaB- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPARgamma activity and insulin responsiveness in human adipocytes.
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PMID:Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. 1687 30

Adiponectin, the most abundantly synthesized protein in adipose tissue, has plieotropic effects on liver, muscle, endothelium, placenta, and other tissues. We examined direct effects of recombinant porcine adiponectin on porcine ovarian granulosa cells in vitro. We demonstrate that adiponectin, at physiologically relevant levels (10-25 microg/ml), provokes expression of genes associated with periovulatory remodeling of the ovarian follicle over a time frame of 6-24 h. These include cyclooxygenase-2, prostaglandin E synthase, and vascular endothelial growth factor. Adiponectin modulates steroid synthetic protein gene expression, increasing steroidogenic acute regulatory protein transcript abundance and reducing cytochrome P450aromatase. Adiponectin has antidiabetic properties and sensitizes tissues to insulin. We show that it interacts with both LH and insulin in inducing expression of cyclooxygenase-2 transcripts in granulosa cells. We determined that the MAPK pathway, via phosphorylation of ERK1/2, is involved in mediation of the adiponectin signal in ovarian granulosa cells, rather than protein kinase A or the classic adiponectin transducer, AMP-activated protein kinase. Adiponectin synthesis is reduced in obesity, and our findings suggest that this reduction plays a role in obesity-related ovarian dysfunction.
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PMID:Adiponectin induces periovulatory changes in ovarian follicular cells. 1691 53

Dragonflies infected with noninvasive gregarine gut parasites (Apicomplexa: Eugregarinorida) [corrected] have reduced flight-muscle performance, an inability to metabolize lipid in their muscles, twofold-elevated hemolymph carbohydrate concentrations, and they accumulate fat in their thorax in a manner analogous to mammalian obesity. Gregarine infection is associated with inappropriate responses of hemolymph carbohydrate concentration to insulin and with chronic activation in the flight muscles of p38 MAP kinase, a signaling molecule involved in immune and stress responses. Short-term exposure to gregarine excretory/secretory products caused elevated blood carbohydrate and p38 MAPK activation in healthy individuals. These characteristics comprise a set of symptoms and processes that are known in mammals as metabolic syndrome but which have not previously been described in other animal taxa. In addition to expanding the known taxonomic breadth of metabolic disease, these results indicate that insects may be useful experimental models for studying its underlying biology and mechanisms.
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PMID:Metabolic syndrome and obesity in an insect. 1713 32

Obesity has been implicated in several diseases, including cancer; however, the relationship of obesity and susceptibility to ultraviolet (UV) radiation-caused skin diseases has not been investigated. As UV-induced oxidative stress has been implicated in several skin diseases, we assessed the role of obesity on UVB-induced oxidative stress in genetically obese Lep(ob)/Lep(ob) (leptin-deficient) mice. Here, we report that chronic exposure to UVB (120 mJ/cm(2)) resulted in greater oxidative stress in the skin of obese mice in terms of higher levels of H(2)O(2) and NO production, photo-oxidative damage of lipids and proteins, and greater depletion of antioxidant defense enzymes, like glutathione, glutathione peroxidase, and catalase. As UV-induced oxidative stress mediates activation of MAPK and NF-kappaB signaling pathways, we determined the effects of UVB on these pathways in obese mice. Exposure of obese mice to UVB resulted in phosphorylation of ERK1/2, JNK, and p38 proteins of the MAPK family. Compared to wild-type mice, the obese mice exhibited higher levels of phosphorylation of these proteins, greater activation of NF-kappaB/p65, and higher levels of circulating proinflammatory cytokines, including TNF-alpha, IL-1beta and IL-6, on UVB irradiation. Taking these results together, our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced oxidative stress and therefore may be a risk factor for skin diseases associated with UVB-induced oxidative stress.
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PMID:Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-kappaB signaling. 1718 35

Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.
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PMID:Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes. 1726 1


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