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)

Adiponectin, an adipocyte-derived hormone, was recently shown to have potential therapeutic applications in diabetes and obesity because of its influence on glucose and lipid metabolism. We found that brown fat in normal human bone marrow contains this protein and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of cyclooxygenase-2 (COX-2) by these stromal cells and induced release of prostaglandin E(2) (PGE(2)). The COX-2 inhibitor Dup-697 prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell-derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from B6,129S(Ptgs2tm1Jed) (COX-2(+/-)) mice. These observations show that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also link adiponectin to the COX-2-dependent PGs that are critical in this process.
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PMID:Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins. 1202 Dec 45

Adiponectin, an adipocyte-derived hormone, is attracting considerable interest as a potential drug for diabetes and obesity. Originally cloned from human s.c. fat, the protein is also found in bone marrow fat cells and has an inhibitory effect on adipocyte differentiation. The aim of the present study is to explore possible influences on lymphohematopoiesis. Recombinant adiponectin strongly inhibited B lymphopoiesis in long-term bone marrow cultures, but only when stromal cells were present and only when cultures were initiated with the earliest category of lymphocyte precursors. Cyclooxygenase inhibitors abrogated the response of early lymphoid progenitors to adiponectin in stromal cell-containing cultures. Furthermore, PGE(2), a major product of cyclooxygenase-2 activity, had a direct inhibitory influence on purified hematopoietic cells, suggesting a possible mechanism of adiponectin action in culture. In contrast to lymphopoiesis, myelopoiesis was slightly enhanced in adiponectin-treated bone marrow cultures, and even when cultures were initiated with single lymphomyeloid progenitors. Finally, human B lymphopoiesis was also sensitive to adiponectin in stromal cell cocultures. These results suggest that adiponectin can negatively and selectively influence lymphopoiesis through induction of PG synthesis. They also indicate ways that adipocytes in bone marrow can contribute to regulation of blood cell formation.
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PMID:Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells. 1460 7

Childhood obesity is prevalent and linked to the development of Type 2 diabetes mellitus (DM) and poor bone health. Some PUFA enhance bone mass and thus may improve bone health in obese children. The study objective was to determine the effects of dietary (n-6) compared with (n-3) essential PUFA and long-chain PUFA (LCPUFA) on bone in an obese and insulin-resistant state. Male fa/fa (n = 48) and lean Zucker rats (n = 48) were fed diets containing safflower oil [SO, high (n-6) PUFA], flaxseed oil [FXO, high (n-3) PUFA], or menhaden oil [MO, high (n-3) LCPUFA] for 9 wk. Measurements included the following: femur bone area (BA), mineral content (BMC), density (BMD), morphometry and ex vivo release of prostaglandin E(2) (PGE(2)); plasma osteocalcin and C-terminal telopeptides of type I collagen. Differences among groups were detected using 2-way ANOVA. Genotype effects in the fa/fa rats included lower femoral weight, length, BA, and BMC, as well as femoral head and proximal epiphysis widths compared with the lean rats, but BMD was not affected. Femur BA, BMC, and BMD did not differ among the dietary groups, but diaphysis width was elevated in the MO group and PGE(2) release was reduced by the FXO and MO diets. No genotype x diet interactions were observed. These data indicate that the fa/fa Zucker rat is at risk for low bone mass and that dietary (n-3) FA effectively reduce PGE(2) release. Whether reduced PGE(2) will support optimal peak bone mass during childhood and conserve bone mass with aging warrants investigation.
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PMID:(n-3) fatty acids reduce the release of prostaglandin E2 from bone but do not affect bone mass in obese (fa/fa) and lean Zucker rats. 1573 84

The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids.
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PMID:Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. 1702 26

With the rising incidence of obesity and the metabolic syndrome, obesity-associated nephropathy also has increased. One of the earliest pathologies in the development of this nephropathy is glomerular hyperfiltration and hypertrophy. Dietary soy protein (SP) ameliorates disease progression in several models of renal disease, and vegetable sources of protein, as compared to animal sources of protein, alter renal hemodynamics. Therefore, the effect of dietary SP on early renal disease and prostanoid production was examined in the obese fa/fa Zucker rat. Rats, 6 weeks of age, were given diets containing 17% protein from either SP or egg white (EW) for 8 weeks. Feed consumption and body and kidney weights were significantly greater in fa/fa rats as compared to lean rats. The fa/fa rats also had 139% more proteinuria and kidneys with 43% larger glomeruli. SP feeding did not alter body weights or proteinuria but did result in 6% lower kidney weights (g/100 g body weight) and 16% smaller glomeruli in fa/fa rats. Cyclooxygenase activity as determined by 6-keto prostaglandin F(1alpha) (6-keto PGF(1alpha)) synthesis was lower in fa/fa rats given SP-based diets as compared to those given EW-based diets. Ratios of renal thromboxane (TX) B(2)/6-keto PGF(1alpha) and PGE(2)/6-keto PGF(1alpha) were higher, while TXB(2)/PGE(2) levels were not different in rats given SP diets as compared to those given EW diets, also indicating that dietary SP reduced renal 6-keto PGF(1alpha) levels. These findings suggest that attenuation of early glomerular hypertrophy in young obese fa/fa rats by dietary SP may be mediated by the lower levels of 6-keto PGF(1alpha) since this would be expected to reduce glomerular hyperfiltration.
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PMID:Dietary soy protein reduces early renal disease progression and alters prostanoid production in obese fa/fa Zucker rats. 1765 81

Optimum but balanced food intake maintains healthy growth and disease-free lifespan. However, imbalanced and over-nutrition promotes obesity, diabetes, malignancy, osteoporosis, infectious diseases, etc. In 1936, McCay reported that calorie restriction prevents weight gain and extend lifespan in rodents. In early 1970, Dr. Good at University of Minnesota and Dr. Walford at UCLA began studies in mice by reducing protein and calorie intake and studying their impact on immune function. Dr. Good's group (Jose, Fernandes, Kramer, Cooper, Day, etc.) reported changes in humoral and cellular immunity at present known as innate and adaptive immune function. Later, much interest was devoted by late Dr. Good on studying the role of calorie restriction (CR) and the role of zinc on immunity, particularly their role on aging, autoimmunity, and malignancy. Both functional role of T-cells, NK-cells and B-cells and their interaction during CR was studied extensively. We recently decided to pursue the beneficial effects of n-3 fatty acids (fish oil) with and without CR on controlling autoimmune-disease in NZB x NZW F1 mice. Our results indicated that n-3 FA when fed ad-libitum prolongs lifespan higher than commonly consumed n-6 FA (corn oil) in these mice. Moreover, n-3 FA + CR is found to be more effective than n-6 FA + CR. Some of the beneficial changes by n-3 FA include enhancing antioxidant enzymes and lowering Th-1/Th-2 cytokines, adhesion molecules, COX-2/PGE(2) levels, pro-inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha etc. The decreased pro-inflammatory cytokines were also found to protect against bone loss in OVX mice. Further, Fat-1 transgenic mice (which make n-3 FA endogenously in vivo from n-6 FA) when fed CR revealed decreased NF-kappaB and AP-1 activity and increased expression of life-prolonging gene SIRT1. Also CR and n-3 FA decreases body weight and increases insulin sensitivity, as well. Thus, to prevent obesity decreased calorie intake with n-3 FA supplement is far more effective and may have protection against CVD, malignancy, autoimmunity, and osteoporosis. The CR studies undertaken in primates and recently in humans are showing very encouraging results. In order to understand more precisely the role of diet and nutrition, new approaches exploring the link through nutrigenomics, proteomics and metabolomics may soon provide insight into controlling age-related diseases by following a balanced food intake.
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PMID:Progress in nutritional immunology. 1825 5

Epidemiological studies indicate that adult-onset asthma is initiated by stress (anxiety and depression), obesity and menopause. Ironically, despite our understanding of the various stressors that promote chronic adult-onset asthma, most of which are known to elevate cortisol production via the hypothalamic-pituitary-adrenal (HPA) axis, inhaled and systemic corticosteroids are the mainstay for the treatment of chronic asthma. This implicates other endocrine or cellular changes independent of cortisol synthesis in non-allergic adult-onset asthma. The mechanism by which corticosteroids are thought to modulate bronchial tone in relieving asthma is via corticosteroid-responsive genes that increase PGE(2) and cAMP production which promote muscle relaxation. Therefore, any physiological condition that suppresses intracellular PGE(2) and cAMP production would counter cortisol-induced muscle relaxation and potentially trigger non-allergic adult-onset asthma. Stress, obesity and menopause act on three interrelated endocrine pathways, the serotonergic, leptinergic and hypothalamic pathways, all of which operate through receptors to modulate cAMP and Ca(2+) metabolism in smooth muscle cells (SMCs). We propose that the level of SMC cAMP, as determined by overall signaling through corticosteroid receptors, leptin receptors and the GPCRs of the HPG and serotonergic pathways, will regulate bronchial tone (i.e. the 'Multi-Hit Endocrine Model of Adult-Onset Asthma'). Thus, decreases in HPG (menopause) and serotonergic (depression) signaling and increases in leptinergic (obesity) signaling relative to HPA signaling would decrease cellular SMC cAMP and promote muscle contraction. This model can explain the discrepant epidemiological data associating stress, obesity, depression and menopause with adult-onset asthma and is supported by basic and clinical data. Treatment of depressed or menopausal asthmatics with selective serotonin reuptake inhibitors or hormone replacement therapy, respectively, alleviates bronchoconstriction. Future therapeutic strategies might therefore target the serotonergic, leptinergic and hypothalamic pathways in regulating cellular cAMP production and bronchoconstriction for the treatment of adult-onset asthma.
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PMID:A multi-hit endocrine model of intrinsic adult-onset asthma. 1837 59

Obesity is associated with asthma and airway hyperresponsiveness. Leptin modulates some of the proinflammatory effects observed in obesity. The objective of this study was to determine the effects of leptin on airway smooth muscle responses. The effect of leptin (0.1-100 ng/ml) on migration (toward platelet-derived growth factor [PDGF], 10 ng/ml, across collagen-coated membrane in Transwell culture plates), proliferation (by BrDU incorporation), and cytokine production (by Bioplex bead assay) of cultured human airway smooth muscle cells from nine nonasthmatic donors was assessed. Effects of leptin on the contractile responses were studied in bovine tracheal smooth muscle rings. Leptin receptor expression and activation of STAT-3, Src kinase, Suppressor of Cytokine Signaling-3 (SOCS-3), and COX were evaluated by Western blotting and PCR. PGE(2) levels in supernatant were assessed by enzyme immunoassay. Human airway smooth muscle cells express leptin receptor, which, when engaged, phosphorylated STAT-3. Leptin inhibited PDGF-induced human airway smooth muscle migration and proliferation and IL-13-induced eotaxin production. Leptin did not stimulate cytokine synthesis and did not evoke contractile responses or inhibit isoproterenol-induced relaxation of carbachol-induced contraction of bovine tracheal rings. The inhibitory effects on migration and eotaxin production are not due to activation of SOCS-3 but are partly due to increased production of PGE(2) because they were attenuated by indomethacin. In conclusion, leptin inhibited human airway smooth muscle proliferation, migration toward PDGF, and IL-13-induced eotaxin production. This is partly mediated by PGE(2) secretion from smooth muscle cells induced by leptin. The association between obesity and asthma is unlikely to be due to a direct effect of leptin on airway smooth muscle.
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PMID:The effects of leptin on airway smooth muscle responses. 1842 Oct 18

Conjugated linoleic acid (CLA) has anti-obesity effects, but induces fatty liver in mice. The present study investigated whether co-administration of arachidonic acid (ARA) attenuates fat accumulation in the mouse liver induced by CLA. Male mice (8 weeks old) were given diets with either no addition of dietary fat (control), 3 % linoleic acid (LA), 3 % CLA, 3 % CLA+1 % ARA, or 3 % CLA+2 % ARA for 4 weeks. The perirenal fat weight in ARA-treated groups decreased similarly as with CLA alone, when compared to control or LA. Plasma TAG concentration was significantly higher in the CLA group than in either CLA+ARA group, while plasma cholesterol and NEFA concentrations did not vary among the groups. In contrast to visceral fat, liver weight was significantly higher in the CLA group than in the control or LA groups, and the effects of CLA were attenuated by ARA. TAG and cholesterol were markedly accumulated in the liver with dietary CLA, whereas co-administration with ARA, at either concentration, suppressed CLA-induced lipid accumulation. Liver PGE(2) was enhanced by a combination of CLA and ARA when compared with CLA alone, but PGE(1) level was not significantly different among groups. In conclusion, fatty liver induced by CLA was attenuated by co-administration with ARA, furthermore, a combination of these fatty acids maintained the anti-obese effect of CLA.
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PMID:Arachidonic acid prevents fatty liver induced by conjugated linoleic acid in mice. 1894 40

In obesity, skeletal muscle blood flow during exercise (functional hyperemia) is impaired. We have indirectly demonstrated that an altered arachidonic acid metabolism is responsible for the impaired functional vasodilation in the obese Zucker rat (OZR), a model of obesity. In this study, we tested the hypothesis that there is an impaired release of PGI(2) due to a nitration of PGI(2) synthase (PGIS), which is associated with a decreased prostanoid receptor expression. PGI(2), PGE(2), and thromboxane A(2) (TXA(2)) release were determined in vitro using ELISA under basal conditions and in response to arachidonic acid (AA) administration (50 microM). Immunofluorescence of PGI(2) and TXA(2) receptors (IP and TP, respectively) was determined in dispersed vascular smooth muscle cells (VSMCs). Nitration of tyrosine residues of the PGIS enzyme was determined using immunoprecipitation and Western blot analysis. Following AA administration, PGI(2) and PGE(2) release were attenuated in OZR compared with lean Zucker rats (LZR; controls). Basal and AA-induced TXA(2) release were not significantly different between groups. IP and TP immunofluorescence were not significantly different between OZR and LZR groups. OZR exhibited elevated nitration of tyrosine residues of PGIS compared with LZR. These results suggest that alterations in the PGI(2) pathway (attenuated PGI(2) synthesis), and not the TXA(2) pathway (normal TXA(2) synthesis/no change in TP receptor expression), underlie the attenuated functional hyperemia in the OZR.
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PMID:Attenuated PGI2 synthesis in obese Zucker rats. 1911 96


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