Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular dysfunction is a major complication of metabolic disorders such as diabetes and obesity. The current studies were undertaken to determine whether inflammatory responses are activated in the vasculature of mice with diet-induced obesity, and if so, whether Toll-Like Receptor-4 (TLR4), a key mediator of innate immunity, contributes to these responses. Mice lacking TLR4 (TLR4(-/-)) and wild-type (WT) controls were fed either a low fat (LF) control diet or a diet high in saturated fat (HF) for 8 weeks. In response to HF feeding, both genotypes displayed similar increases of body weight, body fat content, and serum insulin and free fatty acid (FFA) levels compared with mice on a LF diet. In lysates of thoracic aorta from WT mice maintained on a HF diet, markers of vascular inflammation both upstream (IKKbeta activity) and downstream of the transcriptional regulator, NF-kappaB (ICAM protein and IL-6 mRNA expression), were increased and this effect was associated with cellular insulin resistance and impaired insulin stimulation of eNOS. In contrast, vascular inflammation and impaired insulin responsiveness were not evident in aortic samples taken from TLR4(-/-) mice fed the same HF diet, despite comparable increases of body fat mass. Incubation of either aortic explants from WT mice or cultured human microvascular endothelial cells with the saturated FFA, palmitate (100 micromol/L), similarly activated IKKbeta, inhibited insulin signal transduction and blocked insulin-stimulated NO production. Each of these effects was subsequently shown to be dependent on both TLR4 and NF-kappaB activation. These findings identify the TLR4 signaling pathway as a key mediator of the deleterious effects of palmitate on endothelial NO signaling, and are the first to document a key role for TLR4 in the mechanism whereby diet-induced obesity induces vascular inflammation and insulin resistance.
 ...
PMID:Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. 1755 63

NO plays critical roles in vascular function. We show that modulation of the eNOS serine 1179 (S1179) phosphorylation site affects vascular reactivity and determines stroke size in vivo. Transgenic mice expressing only a phosphomimetic (S1179D) form of eNOS show greater vascular reactivity, develop less severe strokes, and have improved cerebral blood flow in a middle cerebral artery occlusion model than mice expressing an unphosphorylatable (S1179A) form. These results provide a molecular mechanism by which multiple diverse cardiovascular risks, such as diabetes and obesity, may be centrally integrated by eNOS phosphorylation in vivo to influence blood flow and cardiovascular disease. They also demonstrate the in vivo relevance of posttranslational modification of eNOS in vascular function.
 ...
PMID:The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. 1755 22

Human obesity is considered a consequence of a thrifty or economic metabolism. In this hypothesis, we apply an established economic design theory, called symmorphosis, to help explain the known association between obesity and low oxidative capacity skeletal muscle. Symmorphosis reflects an engineering principle, and predicts that physiological systems are most economically designed when unnecessary spare capacity is eliminated. This is because the structural/functional adaptations accounting for spare capacity themselves bear energetic costs of construction, maintenance and load. As oxidation of feed energy occurs in mitochondria, and because skeletal muscle accounts for 30% of resting metabolism, we focus on skeletal muscle mitochondria. In the same way that the most economically designed elevator is supported by a cable that is strong enough, but not too strong, symmorphosis predicts that the most economically designed feed converters should have enough, but not too much mitochondrial oxidative (fuel burning) capacity. While ATP demand is clearly more efficiently met by oxidative (38 molecules of ATP) rather than glycolytic (2 molecules of ATP) metabolism, symmorphosis predicts that having excess oxidative capacity actually reduces feed efficiency. This inefficiency is manifest by having to maintain, ultimately using feed energy, the expensive inner mitochondrial proton gradient in the superfluous mitochondria. On this basis, we predict that established molecular controllers of mitochondrial biogenesis and oxidative capacity such as eNOS, SIN3 co-repressor, TFAM and PPARgamma may yield useful DNA markers and therapeutic targets for issues relating to frugal energetics, namely predisposition to obesity and starvation resilience.
 ...
PMID:Obese humans as economically designed feed converters: symmorphosis and low oxidative capacity skeletal muscle. 1766 46

Metabolic syndrome accelerates the atherosclerotic process, and the earliest event of which is endothelial dysfunction. Ghrelin, a newly discovered gastric peptide, improves endothelial function and inhibits proatherogenic changes. In particular, low ghrelin concentration has been associated with several features of metabolic syndrome, including obesity, insulin resistance, and high blood pressure. However, the molecular mechanisms underlying ghrelin vascular actions remain largely unclear. Here, we showed that ghrelin activated endothelial nitric oxide (NO) synthase (eNOS) in cultured endothelial cells (ECs) and in intact vessels. Specifically, ghrelin rapidly induced phosphorylation of eNOS on an activation site and production of NO in human umbilical vein ECs and bovine aortic ECs. The eNOS phosphorylation was also observed in mouse aortas ex vivo perfused with ghrelin and in aortic tissues isolated from mice injected with ghrelin. Mechanistically, ghrelin stimulated AMP-activated protein kinase (AMPK) and Akt activation in cultured ECs and intact vessels. Inhibiting AMPK and Akt with their pharmacological inhibitors, small interference RNA and adenoviruses carried dominant-negative mutants, markedly attenuated ghrelin-induced eNOS activation, and NO production. Furthermore, ghrelin receptor/Gq protein/calcium-dependent pathway mediates activation of AMPK, Akt, and eNOS, and calmodulin-dependent kinase kinase is a potential convergent point to regulate Akt and AMPK activation in ghrelin signaling. Importantly, eNOS activation is critical for ghrelin inhibition of vascular inflammation. Together, both in vitro and in vivo data demonstrate a new role of ghrelin signaling for eNOS activation, and highlight the therapeutic potential for ghrelin to correct endothelial dysfunction associated with atherosclerotic vascular diseases and metabolic syndrome.
 ...
PMID:Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. 1845 Sep 53

High blood pressure, poor glycemic control, obesity, metabolic syndrome, dyslipidemia, smoking and older age are the risk factors for susceptibility to and initiation of CKD. In these conditions, systemic blood pressure can be transmitted to the glomerular capillary network because of impairment of autoregulationary mechanism existing on the afferent arteriole of glomerulus. Glomerular hypertension and endothelial dysfunction are regarded as the common mechanisms underlying in the development of CKD. Albuminuria reflects the dysregulation of glomerular hemodynamics and vascular damage. Low-grade albuminuria (below the current microalbuminuria threshold) is the independent risk factor for the development of CVD. The renin-angiotensin system(RAS), insulin resistance and increased sympathetic nerve activity are implicated in the development of glomerular hypertension and endothelial dysfunction. Endothelial dysfunction could be caused by decrease of BH4 resultant eNOS uncoupling. Endothelial dysfunction could be regarded as the common mechanisms which link CKD and cardiovascular diseases.
 ...
PMID:[Molecular pathogenesis of chronic kidney disease]. 1878 93

Impairment of vascular growth is a hallmark of diabetic complications, but the progression and mechanisms are poorly understood. To determine whether obesity and early diabetes impair endothelium-dependent vasodilatation and vascular response to ischemia, microvascular function as well as angiogenic responses to ischemia were assessed in young (C57) and 6-month-old lean mice (old C57), in obese (db-C57) mice, and in mice suffering an early (db-KsJ) and sustained type 2 diabetes (old db-KsJ). Glycemia gradually increased from the db-C57 to the old db-KsJ. Early and established type II diabetes significantly reduced the level of insulin that was significantly increased in obese mice. Endothelial function was assessed in isolated resistance arteries while the angiogenic response induced by unilateral hindlimb ischemia was analyzed, after 28 days, with a laser Doppler flowmeter and angiography. Aging (-21%), obesity (-45%), as well as early (-58%) and sustained type II diabetes (-69%) induced a progressive impairment of the endothelium-dependent relaxation of the gracilis artery. Laser Doppler measurements demonstrated that only early and sustained type II diabetes impaired skin blood flow recovery. Vascular collateralization was reduced with aging and severely impaired in older db-KsJ mice, the two strains of mice in which ischemia reduced eNOS expression. These results demonstrate that endothelial dysfunction induced by obesity is insufficient to alter the angiogenic response to ischemia. Furthermore, the development of frank type II diabetes or increasing age is required to impair the vascular response to hindlimb ischemia. We conclude that additional risk factors or severe endothelial dysfunction may be requisite to impede the angiogenic response to ischemia.
 ...
PMID:Obesity induced-insulin resistance causes endothelial dysfunction without reducing the vascular response to hindlimb ischemia. 1954 58

The aim was to assess the relationship between eNOS 4a/b and -786T/C polymorphisms with coronary artery disease (CAD), obesity and diabetes mellitus. Total number of 1313 patients underwent coronary angiography, 939 had significant CAD (stenosis of > or = 1 coronary artery > or = 50%), 222 had smooth coronary arteries. Patients with insignificant atherosclerosis were excluded, the study finally comprised 1161 patients. The analysis of eNOS 4a/b and -786T/ C polymorphisms was performed by polymerase chain reaction. No significant interaction was found between -786T/C polymorphism and solitary CAD or CAD with diabetes and obesity. For 4a/b polymorphism, genotypes aa+ab were almost three times more frequent in diabetic patients without CAD versus patients without CAD and without diabetes--OR 2.79; P = 0.009, Pcorr = 0.03. In 4a/b polymorphism and CAD with obesity and diabetes: bb genotype was significantly more frequent: in patients with CAD, diabetes and obesity in comparison with obese diabetic patients without CAD (OR = 3.63, Pcorr = 0.05); in non-diabetic non-obese patients with CAD, versus diabetic and obese patients without CAD (OR = 3.38, Pcorr = 0.05); in obese non-diabetic patients without CAD vs. obese diabetic patients without CAD (OR = 5.91, Pcorr = 0.01); in patients without CAD, obesity and diabetes vs. obese diabetic patients without CAD (OR = 3.59, Pcorr = 0.05). The eNOS 4a/b polymorphism has significant association with diabetes mellitus in CAD-negative patients, and with CAD in combination with obesity and diabetes mellitus. No association between 4a/b or -786T/C polymorphism and solitary CAD was found.
 ...
PMID:Association of the eNOS 4a/b and -786T/C polymormphisms with coronary artery disease, obesity and diabetes mellitus. 1986 47

Adipocyte dysfunction is associated with the development of obesity. This study shows that 6-thioinosine inhibits adipocyte differentiation. The mRNA levels of PPAR gamma and C/EBPalpha, but not C/EBPbeta and delta, were reduced by 6-thioinosine. Moreover, the mRNA levels of PPAR gamma target genes (LPL, CD36, aP2, and LXRalpha) were down-regulated by 6-thioinosine. We also demonstrated that 6-thioinosine inhibits the transactivation activity and the mRNA level of PPAR gamma. Additionally, attempts to elucidate a possible mechanism underlying the 6-thioinosine-mediated effects revealed that 6-thioinosine induced iNOS gene expression without impacting eNOS expression, and that this was mediated through activation of AP-1, especially, JNK. In addition, 6-thioinosine was found to operate upstream of MEKK-1 in JNK activation signaling. Taken together, these findings suggest that the inhibition of adipocyte differentiation by 6-thioinosine occurs primarily through the reduced expression of PPAR gamma, which is mediated by upregulation of iNOS via the activation of JNK.
 ...
PMID:Anti-adipogenesis by 6-thioinosine is mediated by downregulation of PPAR gamma through JNK-dependent upregulation of iNOS. 1994 Oct 61

Adipocytes are nowadays recognised as cells able to produce and secrete a large variety of active substances termed adipokines, which exert direct effects on vascular cells. Among these adipokines, leptin has been proposed to play a role in the pathophysiology of acute coronary syndromes, as well as in increasing cardiovascular risk. At the moment, however, the mechanisms linking leptin to cardiovascular disease are not completely understood. This study investigates the effects of leptin, in a concentration range usually observed in the plasma of patients with increased cardiovascular risk or measurable in patients with acute coronary syndromes, on tissue factor (TF) and cellular adhesion molecules (CAMs) expression in human coronary endothelial cells (HCAECs). We demonstrate that leptin induces transcription of mRNA for TF and CAMs by real-time PCR. In addition, we show that this adipokine promotes surface expression of TF and CAMs that are functionally active since we observed increased procoagulant activity and leukocyte adhesion on cell surface. Leptin effects appear modulated by eNOS-production of oxygen free radicals through the activation of the transcription factor, nuclear factor(NF)-kappaB, since L-NAME, Superoxide Dismutase and NF-kappaB inhibitors suppressed CAMs and TF expression. Data of the present study, although in vitro , indicate that leptin may exert direct effects on human coronary endothelial cells by promoting CAMs and TF expression and support the hypothesis that this adipokines, besides being involved in the pathophysiology of obesity, might play a relevant role as an active mediator linking obesity to cardiovascular disease.
 ...
PMID:Pro-atherothrombotic effects of leptin in human coronary endothelial cells. 2017 54

Deficiency of adiponectin (APN), an adipocyte-derived vascular protective molecule, contributes to diabetic vascular injury. The current study determined whether obesity/hyperlipidemia may alter the vascular response to APN, and investigated the involved mechanisms and pathologic significance. Adult male Sprague-Dawley rats were fed a regular or high-fat diet (HF) for 4-16 weeks. Circulating APN levels, aortic pAMPK/AMPK, peNOS/eNOS, and APN receptor expression levels were determined. Compared to time-matched animals fed control diet, plasma APN levels in HF-diet animals were significantly increased at 8 weeks, and rapidly declined thereafter. Despite unchanged or elevated circulating APN levels, phosphorylated AMPK and eNOS in vascular tissue were significantly reduced at all observed time points. Recombinant full-length APN (rAPN)-induced AMPK/eNOS phosphorylation and vasodilatation were significantly reduced in 16-week obese/hyperlipidemic aortic segments. Vascular APN receptor 1 (AdipoR1) and receptor 2 (AdipoR2) expression were significantly reduced 16 weeks after HF-diet. Pre-incubation of rAPN with obese/hyperlipidemic plasma, but not with normal plasma, significantly reduced its AMPK and eNOS activation effect, and blunted its protective effect against TNFalpha-induced HUVEC apoptosis. This study demonstrated for the first time that obesity/hyperlipidemia reduces vascular responsiveness to APN. Modification/inactivation of APN by unidentified factors present in obese/hyperlipidemic plasma, decreased vascular AdipoR1/R2 expression, and reduced circulating APN levels contribute to reduced vascular responsiveness to APN at different stages of the obese condition. Reduced APN bioactivity allows unmitigated TNFalpha pro-apoptotic and pro-inflammatory actions, contributing to vascular injury in obesity/hyperlipidemia.
 ...
PMID:Reduced vascular responsiveness to adiponectin in hyperlipidemic rats--mechanisms and significance. 2030 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>