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)

The analysis of 24-h excretion profiles of urinary steroids in 18 patients suffering from Cushing's syndrome or adrenocortical tumors revealed typical patterns when compared to 37 healthy control persons, 24 patients with obesity, and 6 patients with hirsutism. The validation of eight criteria--increased excretion of free cortisol, 6 beta-hydroxycortisol, 20 alpha-dihydrocortisol, 11 beta-hydroxyandrosterone, and 3 beta-hydroxy-5-en steroids, decreased ratio of tetrahydrocortisone (THE) to tetrahydrocortisol (THF), and increased ratios of THF to allotetrahydrocortisol (a-THF) and metabolites of androgens (AM) to metabolites of cortisol (CM)--afforded reliable detection of disorders in steroid biosynthesis. The analysis of urinary steroid profiles can therefore be recommended as a screening procedure in patients with clinical symptoms of disorders in steroid production and/or metabolism.
 ...
PMID:[Urinary steroid profile in Cushing syndrome and in tumors of the adrenal cortex]. 304 Nov

The increasing prevalence of traditional atherosclerotic risk factors have been documented in Asia but the real impact on prevalence of coronary heart disease (CHD) remains unclear. Smoking, hypertension, hypercholesterolaemia, diabetes mellitus and obesity are present in only 50% of CHD. In community studies of Chinese in Hong Kong and southern mainland-China, aging, smoking and hypercholesterolaemia were found to have a less impact on endothelial function in the Chinese compared with Caucasians in London and Sydney. As endothelial dysfunction is an early event in atherogenesis, there will be a strong need to search for newer risk factors for CHD in Asia, which may become more important in many Asian countries now in the process of modernization. Recently, heterozygous hyperhomocysteinaemia (with or without folate deficiency) was found to be an independent risk factor for arterial endothelial dysfunction, and hyperhomocysteinaemia in association with smoking was a significant risk factor for premature coronary heart disease in Hong Kong Chinese. Other newer factors which have emerged include folate deficiency, low HDL-cholesterol, insulin resistance, abdominal obesity, Methylene-tetrahydrofolate Reductase and Angiotensin Converting Enzyme gene polymorphism.
 ...
PMID:New risk factors for coronary heart disease in Asia. 946 82

For a given body mass index (BMI), mortality is higher in patients with central compared to generalized obesity. Glucocorticoids play an important role in determining body fat distribution, but circulating cortisol concentrations are reported to be normal in obese patients. Our recent studies show enhanced conversion of inactive cortisone (E) to active cortisol (F) through the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in cultured omental adipose stromal cells; the autocrine production of F may be a crucial factor in the pathogenesis of central obesity. We have now analyzed F metabolism in subjects with BMIs between 20-25 kg/m2 (group A), 25-30 kg/m2 (group B), and more than 30 kg/m2 (group C; n 12 in each group; six males and six premenopausal females; aged 23-44 yr). Glucose/insulin were measured using a 75-g oral glucose tolerance test, and each subject had total body and regional fat (scapular, waist, hip, and thigh) quantified using dual energy x-ray absorptiometry. Urinary total F metabolites (measured by gas chromatography/mass spectrometry) were increased in subjects with obesity [group A, 11,176 +/- 1,530 microg/24 h (mean +/- SE); group C, 13,661 +/- 1,444], although not significantly so (P = 0.08). There was a significant reduction in the urinary tetrahydrocortisol (THF) +/- 5alpha-THF/tetrahydrocortisone (THE) and the cortol/cortolone ratio in obesity (group A vs. C, 1.06 +/- 0.08 vs. 0.84 +/- 0.04 and 0.41 +/- 0.03 vs. 0.34 +/- 0.03, respectively; both P < 0.05). Urinary free F (UFF) excretion was similar in all three groups, as was the UFF/urinary free E (UFE) ratio. The 0900 h circulating F, E, and ACTH pre- and postovernight 1-mg dexamethasone suppression values were similar in all three groups, but a reduction in the generation of serum F from dexamethasone-suppressed values after oral cortisone acetate (25 mg) was evident in both obese groups [e.g. 546 +/- 37 nmol/L in group A vs. 412 +/- 40 in group B (P < 0.05) and 388 +/- 38 in group C (P < 0.01) 180 min post-E]. Insulin resistance was present in groups B and C, but regression analysis revealed no relationship between F metabolites or the THF +/- 5alpha-THF/THE ratio and insulin action (homeostasis model assessment analysis and insulin values in the oral glucose tolerance test). There was, however, a highly significant relationship between the THF +/- 5alpha-THF/THE ratio and BMI (t = -3.44; P < 0.01) and total body fat (t = -2.27; P < 0.05). Stepwise regression analyses indicated an inverse relationship between THF+/-5alpha-THF/THE and scapular and waist fat (t = -2.25; P = 0.03) and a direct relationship with hip and thigh fat (t = 2.42; P = 0.02) in both sexes. The fall in the THF + 5alpha-THF/THE ratio but unchanged UFF/UFE ratio together with impaired F concentrations after oral E indicates inhibition of 11betaHSD1 in subjects with obesity. This results in an increased MCR for F, explaining the increased F secretion rate in obesity in the face of normal circulating F concentrations. 11BetaHSD1 activity is highly related to body fat distribution, with android or central obesity, but not gynoid obesity, associated with reduced activity in both sexes. This reduction in 11betaHSD1 activity raises new questions as to the primary role of 11betaHSD1 in the pathogenesis of insulin resistance and central obesity.
 ...
PMID:Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. 1008 90

After extensive suprasellar operations for hypothalamic tumor removal, some patients develop Cushing-like morbid obesity while they receive replacement doses of glucocorticoids. In this study, we examined the hypothesis that target tissue conversion of inactive 11-ketosteroids to active 11 beta-OH glucocorticoids might explain the obesity of some patients with hypothalamic lesions. Toward this aim, we studied 10 patients with hypothalamic obesity and secondary adrenal insufficiency and 6 control Addisonian patients while they were on glucocorticoid replacement therapy. Pituitary hormone deficiencies were replaced when medically indicated. Twenty-four-hour urine was collected after a single oral dose of 12 mg/m(2) hydrocortisone acetate. The ratios of free and conjugated cortisol (F) to cortisone (E) and their metabolites, [tetrahydrocortisol (THF)+5 alpha THF]/tetrahyrdocortisone (THE), dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5 alpha THF), were considered to represent 11 beta-hydroxysteroid dehydrogenase (HSD) activity. The 11-OH/11-oxo ratios were significantly higher in the urine of patients with hypothalamic obesity. The 11-OH/11-oxo ratios, however, did not correlate with the degree of obesity, yet a significant correlation was found between conjugated F/E and the ratio of visceral fat to sc fat measured by computerized tomography at the umbilical level. The consequence of increased 11 beta-HSD1 activity and the shift of the interconversion toward cortisol may contribute to the effects of the latter in adipose tissue. We propose that deficiency of hypothalamic messengers after surgical injury induces a paracrine/autocrine effect of enhanced glucocorticoid activity due to up-regulated 11 beta-HSD1 activity.
 ...
PMID:11 beta-Hydroxysteroid dehydrogenase activity in hypothalamic obesity. 1251 80

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.
 ...
PMID:Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. 1467 Nov 89

[Reaction: see text]. The synthesis of neuropeptide Y antagonist 1, currently under clinical investigation for the treatment of obesity, is described. The convergent synthesis from trans-spirolactone carboxylic acid intermediate 2a and aminopyrazole 3 is predicated on a stereoselective route to the former. The coupling reaction of ethyl 4-oxocyclohexanecarboxylate (10a) with lithiated isonicotinamide 11 was investigated in detail, but even optimized conditions only provided a 45:55 ratio of trans:cis isomers (12a:12b). While selective crystallization schemes were developed to isolate the thermodynamically less stable trans isomer 2a, improved stereocontrol was subsequentially achieved by the application of ketene chemistry. The ketene formation and quench was investigated under a variety of conditions aimed at maximizing the trans:cis ratio. Reacting a mixture of carboxylic acids 2a and 2b with POCl3 in THF, followed by concomitant addition of tert-butyl alcohol in the presence of TMEDA at 35 degrees C provided a 4:1 ratio of trans:cis tert-butyl esters (18a:18b) via in situ ketene formation. Ester hydrolysis, followed by selective crystallization of undesired 2b as the HCl salt, led to isolation of 2a in 47% overall yield. Aminopyrazole intermediate 3 was synthesized via the condensation reaction of 2-fluorophenylhydrazine hydrochloride (4a) with acrylonitrile derivative 5 in 65-70% yield. Coupling of advanced intermediates 2a and 3b via activation with thionyl chloride gave a 92% yield of 1.
 ...
PMID:Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene. 1626 94

The development of thromboses is one of the most common causes of morbidity and mortality in the Western world. The perturbation of haemostasis is the central event in the pathogenesis of all thromboses. Most patients with thromboses have no recognisable associated haemostatic disorders. However, some patients do manifest hereditary hypercoagulable states, which contribute to the development of thromboses as well as other clinical manifestations, such as miscarriages and foetal complications. The major determinants of thrombosis include both environmental influences and genetic factors. Transient or long-lasting environmental influences may play important roles in arterial and venous thromboses. Haemostatic perturbance may also be genetically determined and exert a life-long influence. Specific mutations of genes predisposed to thrombosis, such as deficiency of antithrombin, protein C, or protein S, are found in relatively small number of families. In the absence of genetic deficiencies, thrombosis occurs in the older population, largely within the context of marked environmental influences (such as surgery, obesity, and malignancy). In contrast, familial thrombosis, associated with gene mutation, is associated with a younger age. The general importance of gene polymorphism was established after the recognition of activated protein C resistance (APCR) due to gene polymorphism G1691A in factor V (Factor V Leiden). This single gene defect increases the risk of venous thrombosis, without interaction with other genetic or environmental risk factors. The development of APCR led to many other investigations of gene polymorphism, such as prothrombin 20210, thrombomodulin, factors in the coagulation and fibrinolytic system, glycoproteins of platelet membranes, as well as polymorphism C677T of methylene tetrahydrofolate reductase. The number of potential genetic risk factors for occlusive thrombotic disease has increased significantly. Most of these gene polymorphisms increase the risk of venous thrombosis but there is no strong evidence of their influence as far as arterial thrombosis is concerned.
 ...
PMID:[Role of gene polymorphism in development of thromboses]. 1679 67

The Human Genome Project and subsequent identification of single nucleotide polymorphisms (SNPs) within populations has played a major role in predicting individual response to drugs (pharmacogenetics) leading to the concept of "personalized medicine." Nutritional genomics is a recent off-shoot of this genetic revolution that includes (1) nutrigenomics: the study of interaction of dietary components with the genome and the resulting proteonomic and metabolomic changes; and (2) nutrigenetics: understanding the gene-based differences in response to dietary components and developing nutraceuticals that are most compatible with health based on individual genetic makeup. Despite the extensive data on genetic polymorphisms in humans, its translation into medical practice has been slow because of the time required to accumulate population data on SNP incidence, understand the significance of a given SNP in disease, and develop suitable diagnostic tests. Nutrigenomics revitalized the field by showing that nutrients and botanicals can interact with the genome and modify subsequent gene expression, which has provided a great impetus for nutrigenetic research and nutraceutical development based on nutrigenetics. Polymorphisms in methlyene tetrahydrofolate reductase (MTHFR) (involved in folate metabolism), apolipoprotein E (Apo E) and ApoA1 (in cardiovascular disease), and leptin/leptin receptor (obesity) genes are some good examples for understanding basic nutrigenetics. Developing nutraceuticals to prevent and manage thrombosis risk in women with thrombophilic gene mutations are discussed in the context of the opportunities that exist at the nutrigenetic/pharmacogenetic interphase leading to "personalized nutrition." Further research on individual differences in genetic profiles and nutrient requirements will help establish nutrigenetics as an essential discipline for nutrition and dietetics practice.
 ...
PMID:Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine. 1724 Mar 15

Obesity, due to the combination of inherited genes and environmental factors, is continually increasing. We evaluated the relationship between polymorphisms of methylene-tetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), betaine:homocysteine methyltransferase (BHMT G742A) and cystathionine beta-synthase (CBS 68-bp ins) genes and the risk of obesity. We studied these polymorphic variants in 54 normal and 82 obese subjects [body mass index (BMI)=22.4+/-1.8, 34.1+/-7.1; ages 35.2+/-10.7, 43.3+/-10.6 respectively]. Levels of total plasma homocysteine (t-Hcy), folates, and vitamins B6 and B12 were not significantly different, while leptin concentration was significantly higher (p=0.005) in the obese patients compared to the lean controls. The frequency of only (a) MTHFR (AC), (b) MTR (AG), and (c) MTRR (AG) heterozygous genotypes was statistically different in the obese compared to the control group (p=0.03, p=0.007, and p=0.01). Single (a), (b), and (c) heterozygous genotypes had a significant risk of developing obesity [p=0.02, 0.01, and 0.03; odds ratio (OR)=2.5, 3.0, and 2.4; 95% confidence interval (CI)=1.2-5.3, 1.3-7.1, and 1.2-5.1 respectively] and the risk remarkably increased for combined genotypes a+b, a+c, b+c, and a+b+c (p=0.002, 0.002, 0.016, 0.006; OR=7.7, 5.4, 5.8, 15.4; 95% CI=1.9-30.4, 1.7-16.8, 1.4-23.2, 1.6- 152.3). These findings suggest that in obese subjects, Hcy cycle efficiency is impaired by MTHFR, MTR, and MTRR inability to supply methyl-group donors, providing evidence that MTHFR, MTR, and MTRR gene polymorphisms are genetic risk factors for obesity.
 ...
PMID:Are genetic variants of the methyl group metabolism enzymes risk factors predisposing to obesity? 1799 66

Alterations in glucocorticoid (GC) metabolism may contribute to the development of obesity and insulin resistance. We aimed to study the role of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in human adiposity, paying special attention to the association between altered GC metabolism and insulin sensitivity. In 24-h urine samples of 72 extremely obese (mean BMI 45.5 +/- 1.1 kg/m(2)), but otherwise healthy patients urinary free cortisol (UFF), urinary free cortisone (UFE), tetrahydrocortisol (THF), 5alpha-tetrahydrocortisol (5alpha-THF), and tetrahydrocortisone (THE) were quantified by radioimmunoassay. The sum of the three major tetrahydrometabolites is an estimate for daily GC secretion, and the sum of UFF and UFE represents potentially bioactive-free-GCs. Thirty healthy lean subjects (BMI 22.3 +/- 0.3 kg/m(2)) served as controls. In obese subjects, absolute daily GC secretion and the potentially bioactive-free-GCs were significantly (P < 0.005) higher than in lean controls (11.8 +/- 0.7 vs. 8.0 +/- 0.6 mg/d; and 171.8 +/- 11.2 vs. 117.6 +/- 9.2 mug/d, respectively). However, when these values were corrected for body surface area (BSA), significant differences were no longer detectable. While enzyme activity indices for 5alpha-reductase and 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were similar in lean and obese subjects, 11beta-HSD2 was markedly elevated in adiposity (3.7 +/- 0.2 vs. 2.1 +/- 0.1; P < 0.0001). This increase was accompanied by a significant reduction in UFF excretion corrected for BSA (16.5 +/- 1.2 vs. 21.7 +/- 2.0 mug/d/m(2); P = 0.0222). Besides, 11beta-HSD2 activity was significantly correlated with insulin sensitivity (P = 0.0262). When body size is accounted for, both adrenal GC secretion and potentially bioactive-free-GCs are indistinguishable between lean and extremely obese subjects. However in obesity, the kidney appears to intensify its supply of the direct substrate cortisone for extrarenal 11beta-HSD1, which may fuel visceral adiposity and insulin resistance.
Obesity (Silver Spring) 2008 Jun
PMID:11beta-hydroxysteroid dehydrogenase 2 activity is elevated in severe obesity and negatively associated with insulin sensitivity. 1842 Dec 76


1 2 Next >>