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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma leptin levels are elevated in most of obese individuals, and obesity is associated with high incidence of cardiovascular diseases. It has been reported that leptin is an independent risk factor for the coronary artery disease in obese patients and that leptin is involved in the pathogenesis of cardiovascular diseases. We previously reported that leptin promotes platelet aggregation. The present study aimed to elucidate the mechanisms underlying this effect of leptin using a megakaryoblast cell line, MEG-01 cells. Leptin receptors mRNAs expression in MEG-01 cells were analyzed by RT-PCR. Leptin-induced tyrosine-phosphorylation of proteins was analyzed by immunoblotting with an anti-phosphotyrosine antibody. ADP-induced increases in cytosolic Ca(2+) concentration ([Ca(2+)](i)) in the presence and absence of leptin were measured by dual-wavelength fura-2 microfluorometry. Both Ob-Ra and Ob-Rb, were expressed and leptin-induced tyrosine-phosphorylation of several proteins in MEG-01 cells. Leptin-potentiated increases in [Ca(2+)](i) induced by ADP. ADP at a subthreshold concentration and leptin acted synergistically in producing [Ca(2+)](i) increases. These effects of leptin on [Ca(2+)](i) were inhibited by blockers of JAK2 and tyrosine kinases. Furthermore, leptin increased the tyrosine-phosphorylation of Gq alpha-subunits. The results indicate that leptin enhances ADP-induced [Ca(2+)](i) increases via JAK2 and tyrosine kinases in a megakaryoblast cell line. This mechanism may underlie the potentiation of platelet aggregation by leptin.
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PMID:Leptin potentiates ADP-induced [Ca(2+)](i) increase via JAK2 and tyrosine kinases in a megakaryoblast cell line. 1592 98

Glucose transport into muscle is the initial process in glucose clearance and is uniformly defective in insulin-resistant conditions of obesity, metabolic syndrome, and Type II diabetes mellitus. Insulin regulates glucose transport by activating insulin receptor substrate-1 (IRS-1)-dependent phosphatidylinositol 3-kinase (PI3K) which, via increases in PI-3,4,5-triphosphate (PIP(3)), activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). Here, we review (i) the evidence that both aPKC and PKB are required for insulin-stimulated glucose transport, (ii) abnormalities in muscle aPKC/PKB activation seen in obesity and diabetes, and (iii) mechanisms for impaired aPKC activation in insulin-resistant conditions. In most cases, defective muscle aPKC/PKB activation reflects both impaired activation of IRS-1/PI3K, the upstream activator of aPKC and PKB in muscle and, in the case of aPKC, poor responsiveness to PIP(3), the lipid product of PI3K. Interestingly, insulin-sensitizing agents (e.g., thiazolidinediones, metformin) improve aPKC activation by insulin in vivo and PIP3 in vitro, most likely by activating 5'-adenosine monophosphate-activated protein kinase, which favorably alters intracellular lipid metabolism. Differently from muscle, aPKC activation in the liver is dependent on IRS-2/PI3K rather than IRS-1/PI3K and, surprisingly, the activation of IRS-2/PI3K and aPKC is conserved in high-fat feeding, obesity, and diabetes. This conservation has important implications, as continued activation of hepatic aPKC in hyperinsulinemic states may increase the expression of sterol regulatory element binding protein-1c, which controls genes that increase hepatic lipid synthesis. On the other hand, the defective activation of IRS-1/PI3K and PKB, as seen in diabetic liver, undoubtedly and importantly contributes to increases in hepatic glucose output. Thus, the divergent activation of aPKC and PKB in the liver may explain why some hepatic actions of insulin (e.g., aPKC-dependent lipid synthesis) are increased while other actions (e.g., PKB-dependent glucose metabolism) are diminished. This may explain the paradox that the liver secretes excessive amounts of both very low density lipoprotein triglycerides and glucose in Type II diabetes. Previous reviews from our laboratory that have appeared in the Proceedings have provided essentials on phospholipid-signaling mechanisms used by insulin to activate several protein kinases that seem to be important in mediating the metabolic effects of insulin. During recent years, there have been many new advances in our understanding of how these lipid-dependent protein kinases function during insulin action and why they fail to function in states of insulin resistance. The present review will attempt to summarize what we believe are some of the more important advances.
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PMID:Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. 1617 27

Adipogenesis plays a central role in obesity development. The processes of adipogenesis include migration, adhesion, proliferation and survival of preadipocytes and differentiation to mature adipocytes. Many of these biological functions are related to integrins. Here, we found that snake venom-derived arginine-glycine-aspartic acid (RGD)-containing disintegrin inhibited adipogenesis. Rhodostomin but not rhodostomin RGD mutants (RGE-Rn and AKGDWN-Rn) caused the detachment of primary cultured preadipocyte. Furthermore, rhodostomin also inhibited focal adhesion of preadipocyte, including the inhibition of the expression of focal adhesion kinase (FAK) and FAK phosphorylation, assembly of vinculin and reorganization of actin cytoskeleton. Cell viability of preadipocytes was decreased after rhodostomin treatment in a concentration-dependent manner. The results of flow cytometric analysis showed that rhodostomin induced cell apoptosis. In addition, chromatin condensation was observed in DAPI staining. The increase of Bax expression and activation of capsase-3 was detected following rhodostomin treatment. Addition of dexamethasone, IBMX and insulin induced differentiation of preadipocytes into mature adipocytes and treatment of cells with rhodostomin during the initial 3 days showed less mature adipocytes following 9-10 days of differentiating period. The triglyceride content and gene expression of peroxisome proliferators-activated receptor gamma (PPARgamma) and leptin also decreased in response to the treatment of rhodostomin. These results suggest that disintegrin inhibits processes of adipogenesis and may be developed to treat obesity.
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PMID:Inhibition of adipogenesis by RGD-dependent disintegrin. 1619 20

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.
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PMID:Effect of obesity on insulin signaling through JAK2 in rat aorta. 1623 56

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.
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PMID:Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. 1628 52

Increased visceral adipose tissue results in elevated plasma leptin, which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (Apc(Min/+); IMCE) colon epithelial cells but not normal (Apc(+/+); YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells but not in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (P < 0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and associated STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipocyte-specific cytokine leptin and obesity-associated colon cancer.
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PMID:Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line. 1659 43

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

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Tumor necrosis factor-alpha (TNF-alpha) mediated attenuation of insulin signaling pathway is an important cause in several disorders like obesity, obesity linked diabetes mellitus. TNF-alpha actions vary depending upon concentration and time of exposure in various cells. In the present study, the effects of long-term TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1/PKB-alpha (HepG2-CA-Akt/PKB) have been investigated. In parental HepG2 cells, TNF-alpha treatment for 24 h reduced the phosphorylation of Akt1/PKB-alpha and GSK-3beta and under these conditions cells also showed reduced insulin responsiveness in terms of Akt1/PKB-alpha and GSK-3beta phosphorylation. TNF-alpha pre-incubated HepG2-CA-Akt/PKB cells showed lower reduction in Akt1/PKB-alpha and GSK-3beta phosphorylation and insulin responsiveness after 24 h as compared to parental HepG2 cells. We report that the long-term TNF-alpha pre-incubation in both parental HepG2 and HepG2-CA-Akt/PKB-alpha cells leads to the reduction in the levels of IRS-1 without altering the levels of IRS-2. In order to understand the reason for the differential insulin resistance in both the cell types, the effect of long-term TNF-alpha treatment on the proteins upstream to Akt/PKB was investigated. TNF-alpha pre-incubation also showed reduced insulin-stimulated Tyr phosphorylation of insulin receptor (IR-beta) in both the cell types, moreover hyperphosphorylation of IRS-1 at Ser 312 residue was observed in TNF-alpha pre-incubated cells. As hyperphosphorylation of IRS-1 at Ser 312 can induce its degradation, it is possible that reduced insulin responsiveness after long-term TNF-alpha pre-incubation observed in this study is due to the decrease in IRS-1 levels.
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PMID:Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. 1696 Aug 90

The effects of leptin, in concentrations seen in obesity, on collagen production and turnover in non-immortalized human hepatic stellate cell (HSC), were unknown. The profibrogenic effects of leptin in these cells were studied. Hepatic stellate cells were obtained from resected livers. Collagen I/III gene expression and protein production were measured by quantitative real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The signal transduction pathways involved were evaluated by specific blockers of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK), and Janus kinase 2 (JAK2). The effects on matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were assessed by their gene transcript levels, collagenolytic activity of cell culture supernatants, and MMP-1 protein levels. At concentrations seen in nonobese individuals ([leptin] < 10 ng/mL), leptin did not affect collagen production. At concentrations seen in obesity (30-50 ng/mL), leptin increased collagen I and III messenger RNA (mRNA) transcript levels by 286% +/- 55% (P < .001) and 167% +/- 62% (P < .007) and protein production by 45.8% +/- .02% and 84.39% +/- .01%, respectively. These effects were blocked by JAK2 inhibition as well as PI3K inhibition. Although MEK inhibition blocked leptin-induced procollagen I and III mRNA levels, there were no significant effects on collagen I and III protein levels. Leptin (10-50 ng/mL) had no significant effects on MMP-1 or TIMP-1 mRNA levels, collagenolytic activity, or MMP-1 protein levels. In conclusion, leptin, at levels seen in obese individuals, produces an increase in collagen production by HSC acting through the JAK and PI3K pathways. At these concentrations, leptin does not affect MMP-1 or TIMP-1 expression or collagenolytic activity of HSC.
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PMID:Physiologic concentrations of leptin increase collagen production by non-immortalized human hepatic stellate cells. 1697 1


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