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Query: UMLS:C0028754 (obesity)
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Syndrome X is a clinical syndrome in which multiple risks cluster in an individual, and it is a common basis of vascular disease in the industrial countries. The molecular basis of Syndrome X, however, has not been elucidated. We have analyzed body fat distribution using CT scan and have shown that people who have accumulated intra-abdominal visceral fat frequently have multiple risks and vascular diseases. Thus, "visceral fat syndrome" is a clinical entity compatible with Syndrome X. To clarify the molecular mechanism of the disorders in visceral fat syndrome, we analyzed the expressed genes in adipose tissue by a large-scale random sequencing. Unexpectedly, visceral fat expressed a variety of the genes for secretory proteins including various bioactive substances; we designated them adipocytokines. One of them, plasminogen activator inhibitor-1, was overproduced in accumulated visceral fat and might contribute to the development of vascular disease. We have also cloned a novel adipose-specific gene named adiponectin. Adiponectin is a collagen-like plasma protein which has an inhibitory effect on proliferation of vascular smooth muscle cells; its plasma levels are paradoxically decreased in obesity. Adipocytokines may play important roles in the development of the disorders in Syndrome X.
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PMID:Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. 1084 60

The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxonidine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
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PMID:Molecular pathology in the obese spontaneous hypertensive Koletsky rat: a model of syndrome X. 1084 68

A significant number of Americans are at risk for developing a condition of insulin resistance termed Syndrome X. Dyslipidemia, resistance to insulin, obesity, and blood pressure elevation--the deadly quartet--describe Syndrome X, which increases atherogenic risk and contributes to coronary artery disease. Lifestyle factors such as overeating and physical inactivity play a pivotal role in Syndrome X. This deadly duet has been aptly coined "hyperactive fork" and "hypoactive foot," respectively. In addition, emerging evidence suggests that certain nutrients may help protect against Syndrome X. This review provides a brief discussion of diet and lifestyle factors related to Syndrome X.
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PMID:Syndrome X: medical nutrition therapy. 1086 Mar 97

The age-related patterns of clustering of cardiovascular risk variables of Syndrome X from childhood to adulthood were examined in a community-based sample of black and white children (aged 5-10 years, n = 2,389), adolescents (aged 11-17 years, n = 3,371), and young adults (aged 18-37 years, n = 2,115). In the analysis of clustering, insulin resistance index, BMI, triglycerides/ HDL cholesterol ratio, and mean arterial pressure were used either as categorical variables (age-, race- and sex-specific values >75th percentiles) to calculate risk ratios (observed frequency/expected frequency) or as continuous variables (normal scores based on ranks) to compute intraclass correlations. In the total sample, the risk ratio for clustering of adverse levels of all 4 variables was 9.8 for whites (P < 0.01) versus 7.4 for blacks (P < 0.01); the intraclass correlation was 0.33 for whites (P < 0.001) versus 0.26 for blacks (P < 0.001). Both the risk ratio and intraclass correlation were significantly higher in whites than in blacks in the total sample. The intraclass correlations of the 4 variables were significant (P < 0.001) in all race and age-groups, and they were higher during preadolescence and adulthood than during adolescence. Furthermore, unlike risk ratios, intraclass correlations showed a continuous increase with age during adulthood. When BMI was adjusted, the intraclass correlations involving the other 3 variables were reduced by approximately 50%, and the age-related pattern was no longer evident. These results suggest that the degree of clustering of risk variables of Syndrome X varies with age from childhood to adulthood and is likely influenced by the age-related changes in obesity and the attendant insulin resistance.
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PMID:Age-related patterns of the clustering of cardiovascular risk variables of syndrome X from childhood to young adulthood in a population made up of black and white subjects: the Bogalusa Heart Study. 1086 58

We discovered two mouse strains (SMXA-5 and SMXA-9) with hyperinsulinemia among the substrains and progenitor strains (SM/J and A/J) of the SMXA recombinant inbred (RI) strains, and characterized the two strains at 20 weeks of age. SMXA-5 (mean +/- S.E.M: 9.6 +/- 1.7 ng/ml) and SMXA-9 (7.7 +/- 1.3 ng/ml) males had higher serum immunoreactive insulin levels than SM/J (1.4 +/- 0.3 ng/ml) and A/J (1.1 +/- 0.1 ng/ml) males in the nonfasting condition. The hypoglycemic response to insulin at 30 min after injection was significantly less in SMXA-5 males than in SM/J mice. Glucose tolerance test revealed that the incidence of impaired glucose tolerant males was 58% (11/19) in SMXA-5 and 42% (10/24) in SMXA-9 strains, but none in SM/J and A/J strains. SMXA-5 (209 +/- 29 mg/dl) and SMXA-9 (235 +/- 31 mg/dl) had higher serum triglyceride levels than SM/J (126 +/- 14 mg/dl) and A/J (89 +/- 5 mg/dl) males in the nonfasting condition. Histologic examination revealed enlarged islets in the pancreas of hyperinsulinemic SMXA-5 male mice. Moreover, SMXA-5 and SMXA-9 mice exhibited mild obesity. SMXA-5 and SMXA-9 males were therefore characterized by hyperinsulinemia, impaired glucose tolerance, hypertriglyceridemia and mild obesity which resembled some of the phenotypes of human Syndrome X, although both progenitor strains were normal so far as we examined. Since the RI strains are a powerful tool to facilitate polygenic-trait analysis, SMXA-5 and SMXA-9 mice will be useful materials to investigate the genetic basis of complex diseases, and are possible new metabolic models in relation to hyperinsulinemia.
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PMID:Characterization of hyperinsulinemic recombinant inbred (RI) strains (SMXA-5 and SMXA-9) derived from normoinsulinemic SM/J and A/J mice. 1088 46

The cocaine- and amphetamine-regulated transcript (CART) peptide is a recently characterized neuropeptide implicated in the control of appetite. We hypothesized that genetic variation in CART may contribute to human obesity. The entire coding region of CART was determined by nucleotide sequencing in 91 unrelated subjects with severe early-onset obesity. A novel amino acid change, Ser66Thr, was found in 2 probands and in 0 of 100 control subjects but did not cosegregate with obesity in family studies. Two common polymorphisms were found in the 3'-untranslated region (A1475G and deltaA1457). An effect of these polymorphisms on body composition and intermediate phenotypes related to obesity was examined in a large Caucasian population in the U.K. Neither polymorphism showed any significant relationship with obesity; however, men heterozygous for the A1475G variant had significantly lower waist-to-hip ratio (WHR), fasting plasma insulin, and fasting triglycerides. Regression analysis indicated that the effects on insulin and triglycerides were likely to be secondary to the effects on WHR. Thus, we have conducted the first systematic study of the CART gene in human obesity, and although no clear association with obesity was found, the data suggest that genetic variation in the CART locus might influence fat distribution and variables related to syndrome X.
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PMID:The CART gene and human obesity: mutational analysis and population genetics. 1090 99

Multiple metabolic syndrome (MMS) implies a frequent coincidence of four basic serious metabolic risk factors for subsequent manifestation of cardiovascular disease. The latter include: central type obesity, arterial hypertension, dyslipoproteinaemia and diabetes mellitus type II (non-insulin-dependent diabetes mellitus--NIDDM). MMS is also described as syndrome X, Reaven's syndrome, insulin resistance syndrome, metabolic syndrome or as the "deadly quartet". NIDDM in humans is conceived as a syndrome the pathogenesis of which is multifactorial and it is not an unequivocal nosological unit. It many epidemiological studies reliable evidence was provided that in the aetiology of NIDDM a marked genetic influence is involved. Its genetic predisposition is conditioned by the interaction of candidate genes and a complex of influences of the external environment. Evidence was provided that MMS phenotypes cumulate only in members of some families. The mode of genetic transmission of NIDDM remains obscure.
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PMID:[Genetic predisposition for multiple metabolic syndrome. Part 1. Diabetes mellitus type 2--incidence and prevalence]. 1095 28

The insulin resistance syndrome X is related to excess intra-abdominal adipose tissue. With lipectomy of >50% of subcutaneous adipose tissue (SQAT) in nonhibernating, adult female Syrian hamsters on high-fat (HF; 50 calorie%) diet and measurements of oral glucose tolerance, oral [(14)C]oleic acid disposal, serum triglycerides, serum leptin, liver fat, perirenal (PR) adipose tissue cellularity, and body composition, we studied the role of SQAT. Sham-operated (S) animals on HF or low-fat (LF; 12.5 calorie%) diets served as controls. After 3 mo there was no visible regrowth of SQAT but HF diet led to similar levels of body weight and body fat in lipectomized and sham-operated animals. Lipectomized (L) animals had more intra-abdominal fat as a percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum triglycerides compared with S-HF and S-LF. Liver and PR adipose tissue uptake of fatty acid were similar in L-HF and S-HF but reduced vs. S-LF, and were inversely correlated with liver fat content and insulin sums during the oral glucose tolerance test. In summary, lipectomy of SQAT led to compensatory fat accumulation implying regulation of total body fat mass. In conjunction with HF diet these lipectomized hamsters developed a metabolic syndrome with significant hypertriglyceridemia, relative increase in intra-abdominal fat, and insulin resistance. We propose that SQAT, via disposal and storage of excess ingested energy, acts as a metabolic sink and protects against the metabolic syndrome of obesity.
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PMID:Subcutaneous lipectomy causes a metabolic syndrome in hamsters. 1095 51

Childhood obesity is accompanied by a variety of cardiovascular risk factors (hypertension, insulin resistance, dyslipidaemia) which tend to aggregate (syndrome X). 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is supposed to play a role in the pathogenesis of hypertension and the development of syndrome X. There are two isoforms of 11beta-HSD. 11beta-HSD-2 is responsible for the inactivation of cortisol to inactive cortisone. In the case of impaired enzyme activity the ratio of urinary tetrahydrocortisol (THF)+ its isomer allotetrahydrocortisol (5alpha-THF)/tetrahydrocortisone (THE) is elevated. 11beta-HSD-1 is an oxo-reductase, which type catalyses the conversion of cortisone to cortisol. The aim of the present study was to investigate if there was any alteration in the urinary cortisol metabolites reflecting 11beta-HSD activity in hypertensive obese children (no.=15) as compared to normotensive obese (no.=11) and normotensive non-obese children (no.=15). We found an increased excretion of cortisol metabolites in hypertensive obese children compared to obese and normal - weight children having normal blood pressure. The ratio of THF+5alpha(THF/THE had a significant correlation with systolic blood pressure. On the basis of our study the ratio of THF+5alpha-THF/ THE reflecting on altered enzyme activity seems to be an independent factor influencing especially systolic blood pressure in hypertensive obese children.
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PMID:Urinary cortisol to cortisone metabolites in hypertensive obese children. 1100 67

The discovery that insulin resistance has a key role in the pathophysiology of PCOS has led to a novel and promising form of therapy in the form of the insulin-sensitizing drugs. Although no extremely large trials using these drugs for this indication have been performed, more than 18 trials have specifically examined the effects of these drugs on ovulation, hyperandrogenemia, and dysmetabolic features in PCOS. Table 1 summarizes the results of previous trials using each of the insulin-sensitizing drugs discussed herein. Among the various agents (i.e., thiazolidinediones, [table: see text] metformin, and D-chiro-inositol), metformin is the most widely tested. Metformin may have the added benefit of improving at least some features of syndrome X, such as hypertension and obesity. All of the evidence to date suggests that metformin is a safe drug to administer to women who may become pregnant. In contrast, the two thiazolidinediones currently available, rosiglitazone and pioglitazone, are category C drugs that have been demonstrated to retard fetal development in animal studies. Overall, insulin-sensitizing therapy presents a promising and unique therapeutic intervention for the treatment of PCOS, offering metabolic and gynecologic benefits for women who sustain this syndrome.
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PMID:Insulin-lowering drugs in polycystic ovary syndrome. 1129


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