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)

Previous studies in our laboratory demonstrated an altered immuno-endocrine feedback communication via the hypothalamo-pituitary-adrenal (HPA) axis, which may be an important modulatory factor in the development of spontaneous autoimmune thyroiditis in Obese strain (OS) chickens. These birds show a significantly lower, or even absent, increase in serum glucocorticoid levels in response to an intravenous injection of antigen or conditioned medium (CM) from mitogen-stimulated spleen cells known to contain glucocorticoid-increasing factors (GIFs), notably interleukin-1 (IL-1). The present study was aimed at investigating this feedback regulation in animal models with spontaneous systemic autoimmune diseases, such as the UCD-200 chicken, which serves as a model for human scleroderma, and various murine lupus models. In contrast to OS chickens, UCD-200 chickens displayed a nearly normal plasma corticosterone surge in response to CM, and IL-1 was again identified as the primary GIF in CM. Recombinant IL-1 also induced a drastic increase in plasma corticosterone levels in various strains of normal mice. A similar increase was observed in the bacterial lipopolysaccharide-resistant C3H/HeJ strain, thus excluding the possibility of bacterial endotoxin contamination. However, in young lupus-prone (NZB/W)F1 and MRL/MP-lpr mice, a significantly lower increase in plasma corticosterone levels was observed after injection of recombinant IL-1, suggesting a deficient immuno-endocrine communication via the HPA loop in this instance as well. Detailed studies to identify further cytokines with GIF activity in the avian and murine systems showed that both IL-6 and tumor necrosis factor-alpha could induce increased plasma corticosterone levels in mice, but not in chickens. IL-3, IL-8, transforming growth factor-beta, interferon-gamma and granulocyte-macrophage colony-stimulating factor were devoid of GIF activity in both chickens and mice.
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PMID:Disturbed immuno-endocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune disease. 821 76

Plasminogen activator inhibitor-1 is elevated in obesity and may be a risk factor for obesity/NIDDM related cardiovascular disease. In spite of this, little is known about the tissue and cellular origin of elevated PAI-1 in obesity or of the mediators and molecular mechanisms that regulate it. We have begun to systematically address these issues using genetically obese (ob/ob, db/db) mice. Plasma PAI-1 levels were 5-fold higher in obese mice compared to their lean counterparts. Subsequent RT-PCR and in situ hybridization studies suggest that the increased plasma PAI-1 originates primarily from the adipocyte in response to chronically elevated levels of tumor necrosis factor-alpha (TNF-alpha), insulin, and transforming growth factor-beta (TGF-beta). Thus, the signals and mechanisms that lead to elevated plasma PAI-1 observed in obesity are complex, and appear to involve interactions between multiple mediators and the adipose tissue itself.
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PMID:The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM. 919 33

Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.
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PMID:The mahogany protein is a receptor involved in suppression of obesity. 1008 55

It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.
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PMID:GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus. 1031 13

The functions of serotonin have been assigned through serotonin-receptor-specific drugs and mutants; however, because a constellation of receptors remains when a single receptor subtype is inhibited, the coordinate responses to modulation of serotonin levels may be missed. Here we report the analysis of behavioural and neuroendocrine defects caused by a complete lack of serotonin signalling. Analysis of the C. elegans genome sequence showed that there is a single tryptophan hydroxylase gene (tph-1)-the key enzyme for serotonin biosynthesis. Animals bearing a tph-1 deletion mutation do not synthesize serotonin but are fully viable. The tph-1 mutant shows abnormalities in behaviour and metabolism that are normally coupled with the sensation and ingestion of food: rates of feeding and egg laying are decreased; large amounts of fat are stored; reproductive lifespan is increased; and some animals arrest at the metabolically inactive dauer stage. This metabolic dysregulation is, in part, due to downregulation of transforming growth factor-beta and insulin-like neuroendocrine signals. The action of the C. elegans serotonergic system in metabolic control is similar to mammalian serotonergic input to metabolism and obesity.
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PMID:Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. 1067 66

GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes seem to play an important and essential role in the maintenance of glucose homeostasis, and in the pathobiology of obesity and non-insulin dependent diabetes mellitus (NIDDM). Daf-genes encode for proteins which are 35% identical to the human insulin receptor, a transforming growth factor-beta (TGF-beta) type signal and can also enhance the expression of superoxide dismutase (SOD). On the other hand, EFAs and their metabolites can increase the cell membrane fluidity and thus, enhance the expression of GLUT-4 and insulin receptors. In addition, EFAs can suppress TNF-alpha production and secretion and thus, are capable of reversing insulin resistance. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Hence, it is likely that there is a close interaction between GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin that may have relevance to the development of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.
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PMID:GLUT-4, tumour necrosis factor, essential fatty acids and daf-genes and their role in glucose homeostasis, insulin resistance, non-insulin dependent diabetes mellitus, and longevity. 1077 31

Obesity, which has reached epidemic proportions in the United States and other western countries, may be complicated by hypertension, an increased incidence of renal cancer or proteinuria. Patients with obesity-associated proteinuria show focal glomerulosclerosis and glomerulomegaly on biopsy, usually have minimal clinical edema and relatively normal levels of serum albumin, cholesterol and blood pressure, and can progress to end-stage renal disease. Severe obesity may also be an additive risk factor in patients with preexisting nephropathy or reduced renal mass. The pathophysiology of obesity-associated proteinuria is unclear but may include hyperfiltration, increased renal venous pressure, glomerular hypertrophy, hyperlipidemia and increased synthesis of vasoactive and fibrogenic substances, including angiotensin II, insulin, leptin and transforming growth factor-beta1. These substances may individually or interactively affect glomerular hyperfiltration, mesangial cell hypertrophy and matrix production, and the production of collagen, fibronectin, transforming growth factor-beta and other fibrogenic mediators of change. Although angiotensin-converting enzyme inhibition has proven to have an impact, perhaps temporarily, on obesity-associated proteinuria in humans, weight reduction early in the course of the disease would appear the most important therapeutic approach.
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PMID:Obesity and renal disease. 1198 Dec 64

It has been previously shown that 2-hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 micro g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 micro mol/L; P < 0.001) inhibited serum (2.5%)-induced cell growth ((3)H-thymidine incorporation), collagen synthesis ((3)H-proline incorporation), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 micro mol/L) were not blocked by ICI182780 (50 micro mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg + 5 x 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P < 0.05) attenuated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor-beta (TGF-beta) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1(+) cells). 2-OHE had no effects on renal tubular cell TGF-beta, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infiltration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These effects are mediated by estrogen receptor-independent mechanisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis.
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PMID:2-Hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy. 1239 44

Obesity is associated with increased incidence of cardiovascular mortality. However, the mechanisms that link increased fat mass with hypercholesterolemia, hypertension, endothelial dysfunction and coronary heart disease have not been fully elucidated. Unravelling the diverse neuroendocrine systems, which regulate energy balance and body fat has been a long-standing challenge in biology, with obesity as an increasingly important public health focus. Until recently, the adipocyte has been considered only a passive tissue for the storage of excess energy in the form of fat. However, there is now compelling evidence that adipocytes act as endocrine, secretory cells. It has been shown that several hormones, growth factors and cytokines are actually expressed in white adipose tissue. In a dynamic view of the adipocyte a wide range of signals emanates from white adipose tissue such as tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and their respective soluble receptors. White adipose tissue also secretes important regulators of lipoprotein metabolism like lipoprotein lipase (LPL), apolipoprotein E (apoE) and cholesteryl ester transfer protein (CETP). The increasing number of products secreted by adipocytes also includes leptin, estrogen, angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), tissue factor and transforming growth factor-beta (TGF-beta). Nitric oxide synthase (NOS) has been also reported to be expressed in white adipose tissue. Acylation stimulating protein (ASP), adipophilin, adipoQ, adipsin, monobutyrin, agouti protein and factors related to pro-inflammatory and immune processes have also been shown to be released by white adipocytes. Since blood vessels express receptors for most of the adipocyte-derived factors, adipose tissue seems to play a key role in cardiovascular physiology through the existence of a network of local and systemic signals. The current knowledge in this field will be reviewed in the broader perspective of cardiovascular physiology and pathophysiology.
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PMID:The adipose tissue as a source of vasoactive factors. 1532 Jul 86

Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease..
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PMID:Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. 1535 68


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