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The level of fatness at which morbidity increases is determined on an acturial basis. Direct measurements of body fat content, eg hydrodensitometry, bioimpedance or DEXA, are useful tools in scientific studies. However, body mass index (BMI) is easy to calculate and is frequently used to define obesity clinically. An increased risk of death from cardiovascular disease in adults has been found in subjects whose BMI had been greater than the 75th percentile as adolescents. Childhood obesity seems to increase the risk of subsequent morbidity whether or not obesity persists into adulthood. The genetic basis of childhood obesity has been elucidated to some extent through the discovery of leptin, the ob gene product, and the increasing knowledge on the role of neuropeptides such as POMC, neuropeptide Y (NPY) and the melanocyte concentrating hormone receptors (MC4R). Environmental/exogenous factors contribute to the development of a high degree of body fatness early in life. Twin studies suggest that approximately 50% of the tendency toward obesity is inherited. There are numerous disorders including a number of endocrine disorders (Cushing's syndrome, hypothyroidism, etc) and genetic syndromes (Prader-Labhard-Willi syndrome, Bardet-Biedl syndrome etc) that can present with obesity. A simple diagnostic algorithm allows for the differentiation between primary or secondary obesity. Among the most common sequelae of primary childhood obesity are hypertension, dyslipidemia and psychosocial problems. Therapeutic strategies include psychological and family therapy, lifestyle/behavior modification and nutrition education. The role of regular exercise and exercise programs is emphasized. Surgical procedures and drugs used as treatments for adult obesity are still not recommended for children and adolescents with obesity. As obesity is the most common chronic disorder in the industrialized societies, its impact on individual lives as well as on health economics has to be recognized more widely. This review is aimed towards defining the clinical problem of childhood obesity on the basis of current knowledge and towards outlining future research areas in the field of energy homoeostasis and food intake control.
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PMID:Clinical aspects of obesity in childhood and adolescence--diagnosis, treatment and prevention. 1146 94

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.
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PMID:Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. 1147 29

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 +/- 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At weaning, female offspring were assigned to one of two diets (control or hypercaloric [30% fat]). Systolic blood pressure was measured at day 175 and following infusion with 3 microg/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment increased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treatment resulted in a 3- to 5-fold increase in 38--44 kDa and 28--30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin-like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X.
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PMID:IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. 1151 75

This cross sectional study was undertaken to determine whether serum leptin levels were associated with multiple risk factor (MRF) clustering syndrome. We examined the relationship between serum leptin concentrations and blood pressure (BP), serum lipids levels, calculated insulin resistance (HOMA-ratio) and adiposity among 581 Japanese adult women. The serum leptin was increased in female subjects with systolic (> or =160 mmHg) and diastolic > or =90 mmHg) hypertension compared with the normotensive females (mean+/-SE; 9.3+/-0.5 vs 7.7+/-0.3; 10.2+/-0.6 vs 7.1+/-0.3 ng/ml, both p<0.001). Serum leptin was elevated in those with hyper-cholesterolemia (C; > or =220 mg/dl) and triglyceridemia (TG; > or =150 mg/dl) compared with the normolipidemia (9.4+/-0.4 vs 7.8+/-0.3; 11.7+/-0.6 vs 7.5+/-0.2 ng/ml, both p <0.001). Serum leptin was also elevated in those with adiposity (BMI > or =26.4 kg/m2) and insulin resistance (HOMA-ratio > or =2.5) compared with the normal females (14.8+/-0.7 vs 5.2+/-0.2; 11.3+/-1.1 vs 7.1+/-0.4ng/ml, both p<0.001). Even after adjusting for BMI or percent body fat mass (BFM), leptin levels remained to be elevated significantly in all these diseases. There was a positive correlation between serum leptin and systolic, diastolic BP, TC, TG, BMI, BFM, IRI and HOMA-ratio (r=0.12, p=0.005; r=0.24, p<0.0001; r=0.19, p<0.0001; r=0.35, p<0.0001; r=0.72, p<0.0001; r=0.73, p<0.0001; r=0.47, p< 0.0001; r=0.44, p<0.0001), and a negative correlation with HDL-C levels (r= -0.20, p< 0.0001). These correlations were also observed in leptin levels after adjusting for the BMI or BFM. Multiple regression analysis showed that BFM, HOMA-ratio and TG were significant determinants of leptin concentration before (t=12.6, p<0.0001; t=3.33, p=0.001; t=3.22, p=0.001) and after adjusting for BMI or BFM. These results suggest that because serum leptin levels were elevated in components of MRF clustering syndrome, leptin may have a pathophysiological role in MRF clustering syndrome.
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PMID:Elevated serum leptin concentrations in women with components of multiple risk factor clustering syndrome. 1152 87

Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular alpha-helical corticotrophin-releasing factor(9-41) (corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin-releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with alpha-helical corticotrophin-releasing factor(9-41). Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with alpha-helical corticotrophin-releasing factor(9-41). Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions.
Hypertension 2001 Sep
PMID:Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure. 1156 9

Obesity is currently considered as a chronic metabolic disease, associated with a high risk of cardiovascular complications. Leptin, an adipocyte-derived hormone has a variety target cells influencing a wide range of processes. Possible counteractions of hyperleptinaemia are currently investigated. The Na(+)-H(+) exchanger (NHE 1) is involved in multiple cellular functions and its activation has been related to hypertension and obesity. NHE 1 is present on erythrocytes and can be stimulated by various hormones. Erythrocytes have on their surface a variety of receptors with mostly unknown function. In the present paper, the effect of leptin on erythrocytes NHE 1 activity has been investigated. For this reason, the intracellular pH and sodium influxes were measured before and after addition of leptin in erythrocyte suspensions from normal and obese individuals. Amiloride, a specific NHE 1 inhibitor, and staurosporine a protein kinase C inhibitor were used to inhibit erythrocyte NHE 1. For the binding study leptin was labeled with fluorescein isothiocyanate (FITC) and the binding on erythrocytes was estimated by Scatchard analysis. NHE 1 activity increased in the presence of leptin but significantly less in the obese than in the control group. Furthermore the concentrations of leptin binding sites on the surface of erythrocytes were lower in erythrocytes drawn from obese individuals than in erythrocytes drawn from normal subjects. Since NHE 1 activity has been associated with insulin resistance and hypertension, the activation of this antiport by leptin may represent a link between adipose tissue hypertrophy and cardiovascular complications of obesity.
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PMID:The effect of leptin on Na(+)-H(+) antiport (NHE 1) activity of obese and normal subjects erythrocytes. 1160 19

Leptin decreases appetite and increases sympathetic nerve activity and arterial pressure. Recent reports suggest that leptin may also have peripheral vasodilator actions that would tend to reduce arterial pressure. We tested the hypothesis that the direct vascular actions of leptin oppose sympathetically mediated vasoconstriction. We evaluated the effects of intravenous leptin (1 mg/kg over 3 hours) on arterial pressure and mesenteric, hindlimb, and renal blood flows in conscious rats. We then tested whether blockade of nitric oxide or the sympathetic nervous system would unmask a pressor or depressor effect of leptin, consistent with direct vascular actions. Acute intravenous administration of leptin alone did not change arterial pressure or regional blood flows. This was despite a significant increase in lumbar sympathetic nerve activity. Administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester significantly increased arterial pressure and caused vasoconstriction. However, leptin did not have any significant effect on hemodynamics in the presence of N(G)-nitro-L-arginine methyl ester despite continued sympathoactivation. alpha-Adrenoceptor blockade with prazosin alone or combined with yohimbine significantly decreased arterial pressure and caused vasodilation. Again, leptin did not have any effect on arterial pressure or regional blood flow in the presence of sympathetic blockade. These data demonstrate that leptin does not have vasodilator actions in vivo at concentrations that are sufficient to increase sympathetic nerve activity. The absence of a pressor effect of leptin-induced sympathetic activation may merely reflect the brief duration of leptin administration. These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation.
Hypertension 2001 Nov
PMID:Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation? 1171 1

Obesity is a risk factor for many chronic diseases, including glucose intolerance, lipid disorders, hypertension, and coronary heart disease. Even though the body-mass index (BMI) is a heterogeneous phenotype reflecting the amount of fat, lean mass, and body build, several studies have provided evidence of one or two major loci contributing to the variation in this complex trait. We sought to identify loci with potential influence on BMI in the data obtained from National Heart, Lung, and Blood Institute Family Heart Study. Two complementary samples were studied: (a) 1,184 subjects in 317 sibships, with 243 markers typed by the Utah Molecular Genetics Laboratory (UMGL) and (b) 3,027 subjects distributed among 401 three-generation families, with 404 markers typed by the Mammalian Genotyping Service (MGS). A genome scan using a variance-components-based linkage approach was performed for each sample, as well as for the combined sample, in which the markers from each analysis were placed on a common genetic map. There was strong evidence for linkage on chromosome 7q32.3 in each sample: the maximum multipoint LOD scores were 4.7 (P<10-5) at marker GATA43C11 and 3.2 (P=.00007) at marker D7S1804, for the MGS and UMGL samples, respectively. The linkage result is replicated by the consistent evidence from these two complementary subsets. Furthermore, the evidence for linkage was maintained in the combined sample, with a LOD score of 4.9 (P<10-5) for both markers, which map to the same location. This signal is very near the published location for the leptin gene, which is the most prominent candidate gene in this region. For the combined-sample analysis, evidence of linkage was also found on chromosome 13q14, with D13S257 (LOD score 3.2, P=.00006), and other, weaker signals (LOD scores 1.5-1.9) were found on chromosomes 1, 2, 3, 5, 6, 14, and 15.
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PMID:Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. 1171 18

As the world faces an obesity "epidemic," the mechanisms by which overweight is translated into insulin resistance, hypertension, and diabetes need to be better understood. Although the processes of transition remain uncertain, overactivity of the sympathetic nervous system appears pivotal. In obesity, there is stimulation of sympathetic outflow to the kidneys, evident in increased rates of spillover of noradrenaline into the renal veins, and to skeletal muscle vasculature, demonstrated with microneurography. The cause is unclear, but possibly involves the stimulatory action of leptin released from adipose tissue, or from within the brain, for which there is recent evidence in human obesity. The high renal sympathetic tone contributes to hypertension development by stimulating renin secretion and through promoting renal tubular reabsorption of sodium. Neurally mediated skeletal muscle vasoconstriction reduces glucose delivery and uptake in muscle. Impairment of glucose uptake by skeletal muscle is a hallmark of insulin resistance syndromes. Pharmacologic sympathetic nervous suppression within the central nervous system with imidazoline receptor-binding agents such as rilmenidine is a logical therapeutic approach for lowering blood pressure (BP) in patients with essential hypertension, in whom sympathetic activity is often increased. In addition, drugs of this class appear to have the capacity to favorably modify insulin sensitivity, which has particular relevance in the treatment of hypertensive diabetic patients. In the hypertension accompanying maturity onset obesity, with recent recommendations from advisory bodies setting lower goal BP, and with these lower targets often being reached only with combinations of antihypertensive agents, it is advisable that all drugs used in combination therapy have a favorable or at least a neutral effect on insulin resistance.
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PMID:Sympathetic nervous system and insulin resistance: from obesity to diabetes. 1172 88

It is well established that, as a group, patients with essential hypertension are characterized by insulin resistance. Previous studies have shown that a biallelic polymorphism in the tumor necrosis factor (TNF)alpha promoter position -308 and -238 might be involved in the insulin resistance state in diabetic and/or nondiabetic subjects. We determined these polymorphisms in 235 nondiabetic hypertensive subjects and 246 unrelated normotensive controls. Fasting plasma glucose, insulin, lipoprotein, leptin, and TNFalpha concentrations were measured, in addition to plasma glucose and insulin responses to a 75-g oral glucose tolerance test (OGTT). Insulin sensitivity was also determined by an insulin suppression test in 69 hypertensive and 76 normotensive individuals. The results showed no association of these genotypic distributions between hypertensive and normotensive individuals both at -308 (GG, GA, and AA were 80.9%, 17.9%, and 1.3% in hypertensives, 84.2%, 15.4%, and 0.4% in normotensives, chi(2) = 1.68, P =.432) and at -238 (GG, GA, and AA were 98.3%, 1.7%, and 0% in hypertensives, 96.7%, 3.3%, and 0% in normotensives, chi(2) = 1.19, P =.276) sites. These results did not change even after adjustment for values of age and body mass index (BMI). Anthropometric measurements, fasting plasma glucose, insulin, lipoprotein concentrations, glucose, and insulin responses to OGTT, TNFalpha, and leptin concentrations were similar between the genotype at the -308 site both in hypertensive and normotensive groups. Insulin sensitivity, either measured by an insulin suppression test or homeostasis model assessment (HOMA) index, did not differ between the genotype at the -308 site in subjects with hypertension or normotension. Fasting plasma TNFalpha (10.2 alpha 0.5 pg/mL v 10.1 +/- 0.5 pg/mL, P =.928) concentrations did not differ between hypertensive and normotensive subjects even after adjustment for body fat and BMI values. We conclude that TNFalpha promoter gene polymorphisms at position -238 and -308 do not play a major role in the pathogenesis of insulin resistance in Chinese subjects with or without hypertension.
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PMID:Tumor necrosis factor alpha -238 and -308 polymorphisms do not associate with insulin resistance in hypertensive subjects. 1173 91


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