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

The vascular endothelium, building the inner layer of capillaries and blood vessels of all sorts, represents a highly active metabolic and endocrine organ producing a multitude of different molecules, including vasoactive peptide hormones, growth factors, coagulation factors and adhesion molecules. In addition, it expresses many of the respective endocrine, paracrine and cytokine/growth factor receptors. It thereby regulates the delicate balance between vasoconstriction and vasodilation, between coagulation and fibrinolysis, proliferation and apoptosis, as well as between transient adhesion and diapedesis of blood borne leukocytes. This minireview addresses the potential interactions of these important functions in the states of diabetes and of insulin resistance including obesity, hypertension and dyslipidaemia, all of which characterized by endothelial dysfunction.
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PMID:The endothelium as a metabolic and endocrine organ: its relation with insulin resistance. 1146 May 68

Leptin is small cytokine-like protein that is involved in appetite and body weight regulation. Due to increased interest in using leptin as an anti-obesity reagent, recombinant forms of leptin have been produced for several species, including humans, mice, rats, pigs, dogs, sheep etc. The biological activities of such recombinant proteins were determined using various in vitro or in vivo systems; however so far, no specific assay system for rat leptin is available. Since rats are representative animal models in obesity research, the establishment of a biological assay system for determining rat leptin activity has been eagerly awaited. This study describes the generation of such a system using chinese hamster ovary (CHO)-cells that were transfected with the long form of the rat leptin receptor isoform, OB-Rb, whereby a signal transduces and activators of transcription-sensitive luciferase reporter system is further employed to quantify the leptin-mediated signals. This system is the first rat-specific leptin bioassay system that has been reported. It is expected that this assay will be used to further quantify and determine leptin activity from various biological fluids and sources.
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PMID:Determination of rat leptin activity in vitro using a novel luciferase reporter assay. 1156 23

Moderate food and/or energy (calorie) restriction delays age-related immune dysfunction and prolongs life span in multiple animal models. The amount and type of dietary fatty acids can also profoundly affect life span. Marine-derived fish oils contain (n-3) fatty acids, which have potent anti-inflammatory properties. We therefore examined the influence of food restriction (40% overall reduction in intake of all dietary components) combined with substitution of fish oil for corn oil in a factorial design. Autoimmune-prone (NZB x NZW)F(1) (B/W) mice, which develop fatal autoimmune renal disease, were used. The food-restricted/fish oil diet maximally extended median life span to 645 d (vs. 494 d for the food-restricted corn oil diet). Similarly, fish oil prolonged life span in the ad libitum-fed mice to 345 d (vs. 242 for the ad libitum/corn oil diet). Increased life span was partially associated with decreased body weight, blunting renal proinflammatory cytokine (interferon-gamma, interleukins-10 and -12 and tumor necrosis factor-alpha) levels and lower nuclear factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by enhanced superoxide dismutase, catalase and glutathione peroxidase activities. These findings demonstrate the profound additive effects of food restriction and (n-3) fatty acids in prolonging life span in B/W mice. These observations may have additional implications in the management of obesity, diabetes, cancer and/or the aging process.
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PMID:Life span is prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids. 1158

Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for monocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3-5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.
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PMID:High-dose leptin activates human leukocytes via receptor expression on monocytes. 1159 88

SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF-alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance.
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PMID:SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. 1160 92

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.
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PMID:Pro-inflammatory cytokines and adipose tissue. 1168 9

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine with a proposed role in obesity-related insulin resistance. This could be mediated by increased lipolysis in adipose tissue resulting in elevated free fatty acid levels. The early intracellular signals entailed in TNF-alpha-mediated lipolysis are unknown but may involve members of the mitogen-activated protein kinase (MAPK) family. We investigated the possible contribution of MAPK in TNF-alpha-induced lipolysis in human preadipocytes. TNF-alpha activated the three mammalian MAPK, p44/42, JNK, and p38, in a distinct time- and concentration-dependent manner. TNF-alpha also induced a concentration-dependent stimulation of lipolysis with a more than 3-fold increase at the maximal dose. Lipolysis was completely inhibited by blockers specific for p44/42 (PD98059) and JNK (dimetylaminopurine) but was not affected by the p38 blocker SB203580. Use of receptor-specific TNF-alpha mutants showed that activation of MAPK is entirely mediated by the TNFR1 receptor. The results in human preadipocytes differed from those obtained in murine 3T3-L1 adipocytes in which all three MAPK were constitutively active. Thus, studies of intracellular signaling pathways obtained in different cellular contexts should be interpreted with caution. In conclusion, although TNF-alpha activates all three known MAPK in human preadipocytes, only p44/42 and JNK appear to be involved in the regulation of lipolysis.
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PMID:Mapping of early signaling events in tumor necrosis factor-alpha -mediated lipolysis in human fat cells. 1169 22

Primary osteoarthritis (OA) is a polygenic disease associated with age and obesity. In the OA disease setting, abnormal bone anatomy and biomechanics can set off a tissue repair response (intertwined with a mild inflammatory state) that can be seen with the imaging tools of bone scintigraphy and magnetic resonance imaging. This report focuses on weight-bearing OA (knee and hip) and looks at initiating and disease expression events in the subchondral trabecular bone. Multiple drug development targets in soft tissue (cartilage) and hard tissue (bone) can be justified. A successful structure-modifying OA drug (SMOAD) approach that preserves joint structure will likely impact both tissues. The bone and cartilage tissues may signal each other via activation of cytokine pathways and via activation of a generalized tissue repair/mild inflammation response that impacts bone and cartilage.
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PMID:Joint structure modification in osteoarthritis: development of SMOAD drugs. 1170 13

The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.
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PMID:Interleukin-6-deficient mice develop mature-onset obesity. 1178 10

Rich diet and lack of exercise are causing a surge in the prevalence of obesity and hepatic steatosis, which causes "primary" steatohepatitis in some patients. Ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and impaired ability to synthesize ATP are observed in these patients. Reactive oxygen species (ROS) may increase tumor necrosis factor-alpha (TNF-alpha) production and also oxidize fat deposits. TNF-alpha and lipid peroxidation products impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial ROS formation. Steatohepatitis can also be due to alcohol, drugs, or other causes that either directly increase ROS formation or first impair respiration, which secondarily increases ROS formation. Higher ROS formation in secondary steatohepatitis could cause more lipid peroxidation, cytokine induction, and fibrogenesis than in primary steatohepatitis.
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PMID:Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. 1180 39


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