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)

Studies have shown evidence of production of nitric oxide (NO) in adipose tissue, as well as inhibition of lipolysis by NO. We have analyzed nitric oxide synthase (NOS) expression in subcutaneous adipose tissue from 13 nonobese and 18 obese male subjects. Using a competitive reverse transcription polymerase chain reaction method, endothelial (eNOS) and inducible (iNOS), but not neuronal (nNOS), nitric oxide synthase mRNA expression was detected in isolated fat cells and pieces of adipose tissue. Tissue mRNA levels for eNOS were 3,814 +/- 825 and 5,956 +/- 476 amol/mg RNA (P = 0.043), and for iNOS 306 +/- 38 and 332 +/- 48 amol/mg RNA, for nonobese and obese individuals, respectively. Western blotting revealed similar eNOS protein levels in isolated fat cells and adipose tissue pieces. Protein levels for eNOS in nonobese and obese individuals, respectively, were (in optical density [OD] units per mm(2) per 100 microgram of total protein) 0.11 +/- 0.08 and 2.80 +/- 1.30 (P = 0.043). iNOS protein was detectable, but not measurable, at low levels in a subset of obese patients (3 of 10). iNOS protein levels could not be detected in nonobese individuals. Hormone-sensitive lipase (HSL), the key regulating enzyme in lipolysis, is reduced in obesity. The expression of HSL protein in subcutaneous adipose tissue was studied in the same subset of patients; in agreement with previous results, HSL levels were reduced in obese subjects: 4.64 +/- 1.10 and 1.27 +/- 0.35 (P = 0.012) in nonobese and obese subjects, respectively. In conclusion, this study shows that eNOS and iNOS, but not nNOS, are present in human subcutaneous adipose tissue. Gene expression and protein levels of eNOS are increased, whereas HSL protein levels are decreased in obesity. It is speculated that increased NO production, preferably by eNOS, and decreased HSL levels may cause decreased subcutaneous adipose tissue lipolysis in obesity. synthases in subcutaneous adipose tissue of nonobese and obese humans.
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PMID:Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans. 1094 12

Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPARgamma ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)-->Akt-->eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPARgamma-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPARgamma-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPARgamma-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K-->Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPARgamma-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.
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PMID:Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. 1241 72

A link between leptin resistance, obesity, and salt sensitivity has been suggested. SHHF/Mcc-fa(cp) rats (SHHF) were used to study the effect of gene dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and response to a combined endothelin A and B receptor antagonist (bosentan). Obese (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7 days. There were no significant differences in systolic blood pressure between genotypes on low salt. In response to high salt, cp/cp had significantly greater systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a significant increase in 24 h urinary endothelin excretion and increased renal expression of preproendothelin mRNA. There was no effect of high salt diet on renal excretion of nitric oxide (NOx) or on gene expression of endothelial, neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS, respectively). Treatment with bosentan prevented the high salt-induced increment in systolic blood pressure in cp/cp. This was associated with a doubling of renal NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin receptor antagonism did not normalize systolic pressure in any of the genotypes. Our studies indicate that obesity secondary to leptin resistance (cp/cp) results in increased salt sensitivity that is mediated by endothelin in the SHHF rat.
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PMID:Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin. 1261 66

Adipose tissue generates many bioactive substances, which may exert autocrine, paracrine and endocrine effects. Recent studies have revealed, that one of these substances is nitric oxide. There are observed increased expressions of synthases NO (eNOS and iNOS) in adipose tissue in obesity. It seems that these increased expression NOS is reflected by increased serum concentration of NO in obese subjects. The review of the current literature on role of nitric oxide in physiology and pathology metabolism is presented in this paper.
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PMID:[Nitric oxide in physiology and pathology of metabolism]. 1585 60

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

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.
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PMID:Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. 1650 32

In chronic heart failure of CAD, therapeutic approach will be available either with drugs or exercise. With exercise, coronary risk factors such as BP, lipid, DM and obesity will be controlled. In addition, ischemia will also be controlled by decreasing oxygen demand related to BP and HR, and with increasing oxygen supply by increased ECNOS gene expression, collateral formation and regression of coronary stenosis. Infarct size is also reported to be decreased by increasing MnSOD in the cell by exercise. Prognosis of CHF is also good in various evidence of exercise therapy. Recent advances of molecular biology have revealed various mechanisms of exercise effect. Thus, exercise if properly prescribed without provoking ischemia will be basically and clinically effective therapy for patients with CHF.
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PMID:[Exercise therapy for heart failure]. 1668 81

Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
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PMID:TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. 1698 Oct 10

There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO. Translating the preclinical discoveries in NO biology to new modalities for disease management has not been as impressive. Beyond the success of drugs for erectile dysfunction, clinical trials of nitric oxide synthase inhibitor have been proven either ineffective or wrought with side effects. NO donors (e.g., nitroglycerine) remain frequently used cardiovascular agents, but were discovered before 1980. Gene therapy studies have yet to become clinically useful. There is no doubt that endothelial- and NO-dysfunction is a hallmark of cardiovascular disease, including diseases which are considered as major current public health concerns: hypertension, obesity, diabetes, malnutrition. In many cases, cardiovascular disease (CVD) can be prevented by identifying and controlling modifiable risk factors. One conceivable approach to the management of multiple risk factors in CVD could be to treat endothelial dysfunction (e.g., by enhancing eNOS expression), since many CVD risk factors are related to endothelial dysfunction. In this regard one goal may include optimizing eNOS function. This can be realized by supplementing co-factors, e.g., BH4, or substrate, L-arginine, by increasing cGMP availability via phosphodiesterase inhibitors or sGC activators or by increasing NO bioavailability via antioxidants. The association of other proteins with the nitric oxide synthase (NOS) isoforms and sGC could also serve as experimental and potentially therapeutic targets to modulate NO bioactivity. There is tremendous promise behind NO itself as well as the numerous other molecules and processes associated with the L-arginine-NO-cGMP pathway. Collaborative efforts among bench scientists, clinical investigators and epidemiologists are the key in realizing this promise.
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PMID:Nitric oxide and the endothelium: history and impact on cardiovascular disease. 1705 61

Obesity is a well-known risk factor for erectile dysfunction, which is associated with reduced penile nitric oxide synthase (NOS) expression. Recently it was reported that metformin activates AMP-activated protein kinase (AMPK), which increases the expression of neuronal (n) NOS and endothelial (e) NOS. Thus, to evaluate whether metformin restores NOS expression in penile tissue, we measured penile expression of nNOS and eNOS after 4 weeks of metformin treatment (300 mg/kg/d) in 5-month-old high-fat-fed obese (HFO) rats. HFO rats have increased fat accumulation in visceral areas and marked suppression of nNOS and eNOS expression in penile tissue. However, metformin treatment decreased visceral fat deposition and restored nNOS and eNOS expression in penile tissue. The levels of AMPK and phosphorylated AMPK were also decreased in HFO rats but were subsequently elevated by metformin treatment. These results suggest that expression of NOS was suppressed by the high-fat diet but restored by metformin treatment. The effect of metformin on the expression of NOS may be associated with its activation of AMPK.
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PMID:Metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. 1731 35


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