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)

Leptin serum levels are about 5 times higher in obese people than in normal individuals. We aimed at investigating the signaling pathways induced by leptin in the human colonic cell lines LS174T and HM7. Both cells expressed the leptin transmembrane Ob-receptor. Leptin activated the mitogen-activated protein kinase pathway, induced invasion of colonic cells and concomitantly increased the formation of lamellipodial structures. A direct and novel dose- and time-dependent activation of RhoA, Cdc42 and Rac1 by leptin is demonstrated in these aggressive colon cancer cells. The activation of the Rho family of GTPases was amenable to specific inhibition: Wortmannin inhibited leptin-induced Rac1 and Cdc42 activation but did not affect RhoA activation, and inhibited the formation of leptin-induced lamellipodia and cell invasion. The Rac1 inhibitor NSC23766 inhibited only leptin-induced Rac1 activation and concomitantly, lamellipodium formation and cell invasion. The Src kinase inhibitor II (SrcKI-II) exerted a positive effect on RhoA activation, inhibited tyrosine phosphorylation of p190RhoGAP and inhibited leptin-induced Cdc42 activation and leptin-induced lamellopodium formation and cell invasion. The specific JAK2 inhibitor AG490 exerted a positive effect on Rac1 and Cdc42 activation by leptin and concomitantly inhibited RhoA activation. AG490 did not inhibit leptin-induced lamellopodium formation or cell invasion. Our findings clearly indicate that leptin activates PI3K and Src kinase pathways in the metastatic colon cancer cells LS174T and HM7. These signaling pathways induce the activation of Rac1 and Cdc42, lamellopodium formation and concomitantly enhanced cell invasion, but leptin activation of RhoA is not associated with enhanced cell locomotion and invasion. Understanding in-depth the pathways involved in leptin-associated enhanced cell locomotion and invasion may contribute with the design of novel therapeutics to treat obesity-associated advanced colorectal cancer.
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PMID:Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways. 1876 36

White adipose tissue (WAT) in obese humans is characterized by macrophage accumulation the effects of which on WAT biology are not fully understood. We previously demonstrated that macrophage-secreted factors impair preadipocyte differentiation and induce inflammation, and we described the excessive fibrotic deposition in WAT from obese individuals. Microarray analysis revealed significant overexpression of extracellular matrix (ECM) genes in inflammatory preadipocytes. We show here an organized deposition of fibronectin, collagen I, and tenascin-C and clustering of the ECM receptor alpha5 integrin, characterizing inflammatory preadipocytes. Anti-alpha5 integrin-neutralizing antibody decreased proliferation of these cells, underlining the importance of the fibronectin/integrin partnership. Fibronectin-cultured preadipocytes exhibited increased proliferation and expression of both nuclear factor-kappaB and cyclin D1. Small interfering RNA deletion of nuclear factor-kappaB and cyclin D1 showed that these factors link preadipocyte proliferation with inflammation and ECM remodeling. Macrophage-secreted molecules increased preadipocyte migration through an increase in active/phosphorylated focal adhesion kinase. Gene expression and neutralizing antibody experiments suggest that inhibin beta A, a TGF-beta family member, is a major fibrotic factor. Interactions between preadipocytes and macrophages were favored in a three-dimensional collagen I matrix mimicking the fibrotic context of WAT. Cell-rich regions were immunostained for preadipocytes, proliferation, and macrophages in the vicinity of fibrotic WAT from obese individuals. In conclusion, an inflammatory environment leads to profound modifications of the human preadipocyte phenotype, producing fibrotic components with increased migration and proliferation. This phenomenon might play a role in facilitating the constitution of quiescent preadipocyte pools and eventually in the maintenance and aggravation of increased fat mass in obesity.
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PMID:Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. 1894 11

Obesity is associated with chronic low-grade inflammation. It is currently hypothesized that products secreted from fat cells not only cause this proinflammatory condition but may also have a direct impact on the development of insulin resistance in skeletal muscle. The aim of this study was to investigate if adipocyte-conditioned media interfere with insulin-stimulated Akt/PKB phosphorylation in in vitro differentiated human skeletal muscle cells. Primary human skeletal muscle cells were exposed to adipocyte-conditioned media from subjects with a wide range of BMI. Insulin-induced phosphorylation of the signaling proteins Akt/PKB and ERK-2 was analyzed using a bead-based fluorescence detection system and was correlated to BMI and fat cell size. Adipocyte-conditioned media reduced insulin-stimulated Akt/PKB phosphorylation in a manner depending on BMI and fat cell volume. This inhibition in serine phosphorylation was comparable to that observed in TNF-alpha-treated control cultures. Conditioned media from omental adipocytes reduced Akt/PKB phosphorylation moderately to a greater extent compared to media from subcutaneous fat cells from the same donors (p<0.05). Furthermore, there were significant associations between the concentration of selected adipokines and Akt/PKB phosphorylation. These data provide first direct evidence that secreted factors from freshly isolated mature fat cells separated according fat cell size reduce insulin-stimulated Akt/PKB phosphorylation in human skeletal muscle cells and may contribute to the pathogenesis of obesity-associated insulin resistance.
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PMID:Effect of conditioned media from mature human adipocytes on insulin-stimulated Akt/PKB phosphorylation in human skeletal muscle cells: role of BMI and fat cell size. 1895 3

Thyroid hormones exert most of their physiological effects through two thyroid hormone receptor (TR) subtypes, TRalpha and TRbeta, which associate with many transcriptional coregulators to mediate activation or repression of target genes. The search for selective TRbeta ligands has been stimulated by the finding that several pharmacological actions mediated by TRbeta might be beneficial in medical conditions such as obesity, hypercholesterolemia and diabetes. Here, we present a new methodology which employs surface plasmon resonance to investigate the interactions between TRbeta ligand binding domain (LBD) complexes and peptides derived from the nuclear receptor interaction motifs of two of its coregulators, SRC2 and DAX1. The effect of several TRbeta ligands, including the TRbeta selective agonist GC-1 and the TRbeta selective antagonist NH-3, were investigated. We also determined the kinetic rate constants for the interaction of TRbeta-T3 with both coregulators, and accessed the thermodynamic parameters for the interaction with DAX1. Our findings suggest that flexibility plays an important role in the interaction between the receptor and its coregulators, and point out important aspects of experimental design that should be addressed when using TRbeta LBD and its agonists. Furthermore, the methodology described here may be useful for the identification of new TRbeta ligands.
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PMID:Ligand induced interaction of thyroid hormone receptor beta with its coregulators. 1900 Jul 67

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21-24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-kappaB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p<0.05), p66Shc/phospho-p66 (p<0.05), Bax/Bcl-2 ratio (p<0.05) and NF-kappaB expression (p<0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p<0.001) and WKYs (p<0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD.
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PMID:Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease. 1904 34

Clinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n = 40; BMI, 41.6 +/- 1.1 kg/m2; leptin, 49.7 +/- 3.4 ng/ml) in comparison to normal-weight controls (n = 36; BMI, 23.3 +/- 0.4 kg/m2; leptin, 6.5 +/- 0.7 ng/ml). The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 microM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p = 0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADP-induced platelet aggregation.
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PMID:Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity. 1913 16

The state of child and adolescent overall health in the United States evidences the need for both prevention and treatment. Although much time and energy has been spent in recent years discussing and improving health benefit coverage and affordability for children, physical access to services has not kept pace with these changes. This article will introduce four major physical health issues (obesity, diabetes, asthma, and teen pregnancy/STD) and five key mental health issues (suicide, depression, ADHD, aggression, and violence) facing young people today. In an effort to answer the question, "What can be done?" school-based health clinics and their impact on health and educational outcomes are examined.
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PMID:Bridging the gap from availability to accessibility: providing health and mental health services in schools. 1919 36

Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-lambda knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFkappaB (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkappaB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkappaB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.
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PMID:The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity. 1920 34

Mesenchymal stem cells (MSCs) are self-renewable multipotent progenitor cells with the capacity to differentiate into several distinct mesenchymal lineages. While MSCs display significant potential in tissue engineering and therapeutic applications, the regulatory mechanisms underlying the differentiation of these cells are yet to be established. Phosphorylation is a post-translational modification that plays a significant role in diverse biological phenomena. In this study, to mine the protein tyrosine phosphatases (PTPs) involved in adipogenesis of human MSCs, differential expression of human PTPs was examined using RT-PCR analysis. Among the 107 human PTPs, PTP-RQ was dramatically downregulated during the early phase of adipogenesis. PTP-RQ is classified as a receptor-type III PTP with phosphatidylinositol phosphatase (PIPase) activity. Overexpression of PTP-RQ consistently led to reduced differentiation of MSCs into adipocytes via decreasing the phosphatidyl inositol phosphate level in cells, and consequently downregulating Akt/PKB phosphorylation. Our results collectively suggest that PTP-RQ is a useful target protein for regulating the differentiation of MSCs into adipocytes, and may be used to develop novel drugs for the treatment of obesity.
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PMID:Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells. 1935 28

In diet-induced obese rats, leptin-mediated natural killer (NK) cell activation has been demonstrated to be impaired by abrogated intracellular JAK2-STAT3 signaling. The contribution of the obese microenvironment to this NK cell dysfunction and its reversibility remains elusive. In this study, the functions of NK cells from diet-induced obese rats after adoptive transfer into lean littermates were investigated using in vivo and in vitro approaches. Endogenous NK cells of normal-weight and diet-induced obese F344 rats were depleted in vivo. Then, NK cells from either normal-weight or obese donors were transferred. The numbers of peripheral blood NK cells were analyzed by fluorescence-activated cell sorting (FACS) and the distribution pattern of NK cells in lung and spleen by immunohistochemistry. Ob-R expression was evaluated by immunohistology and activation of intracellular target proteins of Ob-R by immunoblotting. The numbers of NK cells in blood and lung were significantly higher in obese animals compared to lean ones after transfer of NK cells from obese F344 rats. This was correlated with increased postreceptor signaling (JAK-2p, PKBpT308, ERK-2p) without altered Ob-R expression in those NK cells transferred to lean (ob-->nw) vs. obese (ob-->ob) animals. These results show for the first time that the altered phenotype of NK cells from obese rats can be normalized by generation of a physiological (metabolic) environment of lean rats.
Obesity (Silver Spring) 2009 Oct
PMID:Altered phenotype of NK cells from obese rats can be normalized by transfer into lean animals. 1944 29


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