Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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1. Seven subjects were studied before and after the rate of cholesterol synthesis was altered with drugs or dietary cholesterol. 2. The rate at which plasma free cholesterol was formed from squalene during constant infusions of radioactive mevalonate increased with colestipol treatment, decreased with clofibrate treatment and decreased when cholesterol was added to the diet. The plasma squalene concentration showed corresponding changes, confirming that its measurement may qualitatively define changes in cholesterol synthesis. 3. The mean plasma squalene concentration in seven hypertriglyceridaemic, slightly overweight subjects was significantly higher than in six hypercholesterolaemic subjects, which is consistent with other evidence for increased cholesterol synthesis in hypertriglyceridaemia.
Clin Sci Mol Med 1975 Dec
PMID:Plasma squalene as an index of cholesterol synthesis. 120 94

Psychometrically defined restrained eaters consume fewer calories, take fewer meals, show higher preference for low calorie foods, have lower energy expenditure and a higher rate of ovarial dysfunction than unrestrained eaters. We hypothesized that restrained eaters as assessed with the factor cognitive restraint of the Three-Factor Eating Questionnaire have low leptin levels; therefore, we measured serum leptin levels in 136 underweight students and 49 overweight students, who had filled out the Three-Factor Eating Questionnaire. Body mass indexes, fat mass and percent body fat were determined. Spearman correlations revealed that log10 leptin levels of only the 67 underweight females were negatively correlated with cognitive restraint scores (r = -0.5; nominal P-value < 0.001). The restraint score explained 22% of the total variance of leptin levels in underweight females; in combination with percent body fat, 52% of the variance was accounted for. To our knowledge this is the first study to identify a relationship between a score on a psychometric scale and leptin levels. Restrained eating has a biological correlate in underweight females.
Mol Psychiatry 1997 Sep
PMID:Restrained eating is associated with low leptin levels in underweight females. 932 39

Obesity is a highly prevalent disease that carries enormous human and economic costs in western nations. The complexity and diversity of the paths leading to an overweight or an obesity status are enormous. The etiology, causes, associated morbidity, treatment, benefits versus risks of weight loss, prevention, and other aspects of obesity are all highly complex and intimately associated with other diseases, the prevalence of which is augmented by our present way of life. This article gives a brief overview of the current status of knowledge of the genetic basis of human obesity from a genetic epidemiology, experimental genetic and molecular biology perspective. It appears likely that the susceptibility to obesity depends, to a large extent, on several autosomal genes.
Mol Med Today 1995 Apr
PMID:The genetics of obesity: from genetic epidemiology to molecular markers. 941 38

Insulin Sensitivity Indices for glycemia [ISI(gly)] and blood FFA [ISI(ffa)] can be calculated with the formulas: ISI(gly) = 2/[(INSp x GLYp) + 1], and ISI(ffa) = 2/[(INSp x FFAp) + 1], where INSp, GLYp and FFAp = insulinemic, glycemic, and FFA areas during OGTT (75 g glucose) of the person under study, simplified by considering only data at 0 and 2 h (0-2 h areas), according to WHO criteria or, better, at 0, 1 and 2 h (0-1-2 h areas). Expressed as unit/ volume.h-1, 0-1-2 h area is equal to 1/2 value at 0 min + value at 1 h + 1/2 value at 2 h, while 0-2 h area is equal to value at 0 + value at 2 h. Instead of areas, basal levels can also be used. Basal levels and areas are expressed taking the mean normal value as unit, so that in normal subjects ISI(gly) and ISI(ffa) are always around 1, with maximal variations between 0 and 2. Each laboratory should have its normal reference values for basal levels and OGTT areas. However, reliable mean normal values were selected from literature. Based on meta-analysis of published data, ISI(gly) and ISI(ffa) were reduced in subjects who were overweight and/or IGT and in NIDDM patients and their relatives. Moreover, correlation of ISI(gly) with the euglycemic clamp data was significant. However, it should be stressed that the clamp procedure is performed under artificially induced steady-state whereas ISI(gly) and ISI(ffa) are obtained under rather physiological conditions, with hormonal and metabolic variables unmodified, thus being suitable to assess whole-body insulin sensitivity in the clinical setting.
Mol Genet Metab 1998 Feb
PMID:Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. 956 67

The tumour necrosis factor (TNF)2 allele appears to be linked with increased insulin resistance and obesity, conditions often found in overweight patients with polycystic ovary syndrome (PCOS). The significance of TNFalpha polymorphism in relation to the clinical and biochemical parameters associated with PCOS was investigated in 122 well-characterized patients with polycystic ovaries (PCO). Of these, 84 had an abnormal menstrual cycle and were classified as having PCOS, while the remaining 38 had a normal menstrual cycle and were classified as having PCO. There were a further 28 individuals without PCO (non-PCO) and 108 individuals whose PCO status was undetermined (reference population). The promoter region of the TNFalpha gene was amplified by polymerase chain reaction (PCR), and the presence or absence of the polymorphism at -308 was determined by single-strand conformational polymorphism (SSCP) analysis. The less common TNF allele (TNF2) was found as TNF1/2 or TNF2/2 in 11/38 (29%) of PCO subjects, 25/84 (30%) of PCOS subjects, 7/28 (25%) of non-PCO subjects, and 45/108 (42%) of the reference population. There was no significant difference in the incidence of the TNF2 allele between the groups. The relationship of TNF genotype to clinical and biochemical parameters was examined. In both the PCO group and the PCOS group, the presence of the TNF2 allele was significantly associated with lower glucose values obtained from the glucose tolerance testing (P<0.05). The TNF genotype was not significantly associated with any clinical or biochemical parameter measured in the PCO, PCOS or non-PCOS groups. Thus, the TNFalpha -308 polymorphism does not appear to strongly influence genetic susceptibility to polycystic ovaries.
Mol Hum Reprod 1999 Jan
PMID:No association between the -308 polymorphism in the tumour necrosis factor alpha (TNFalpha) promoter region and polycystic ovaries. 1005 Jun 54

The insulin receptor substrate-2 (IRS-2) is a major insulin signalling molecule. IRS-2 inactivation in mice induces a form of diabetes characterized by peripheral insulin resistance and reduced beta cell mass. We tested the hypothesis that a common non-conservative amino acid substitution of IRS-2 (G1057D) might interact with overweight in the pathogenesis of type 2 diabetes. The variant was genotyped in 193 Italian patients with type 2 diabetes and 206 control subjects. In the absence of overweight, the risk of type 2 diabetes decreased according to the dosage of the D1057 allele (odds ratio for GD genotype 0.46 [95% CI 0.25-0.86]; DD genotype 0.18 [0.04-0.68]; P for trend = 0.0012). Conversely, the interaction between overweight and genotype increased the risk of type 2 diabetes according to the dosage of the D1057 allele (odds ratio for GD genotype 2.50 [1.11-5.65]; DD genotype 5.74 [1.11-29. 78]; P for trend = 0.0047). Among controls, fasting C-peptide levels, after adjustment for plasma glucose, were inversely related to the dosage of the D1057 allele (P = 0.020). This finding suggested that carriers of the D1057 allele may have higher insulin sensitivity and supported the protective effect of this allele. Conversely, among overweight patients there was a parallel increase in fasting plasma glucose (P for trend = 0.037) and fasting C-peptide according to the dosage of the D1057 allele, suggesting that higher insulin resistance and relative beta cell failure contributed to the increased risk of type 2 diabetes in overweight carriers of this allele. These data provide evidence for a strong association between type 2 diabetes and the G1057D common genetic variant of IRS-2, which appears to be protective against type 2 diabetes in a codominant fashion. Overweight appears to modify the effect of this polymorphism toward a higher risk of type 2 diabetes. Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive weight.
Hum Mol Genet 2000 Oct 12
PMID:Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. 1103 Jul 56

The insulin-like growth factor 2 gene (Igf2) is imprinted in most somatic tissues of the mouse with the exception of the choroid plexus and leptomeninges of the brain, where it is expressed from both alleles. The imprinting of Igf2 is dependent upon an imprinting control region (ICR) that lies 90 kb 3' of the gene and acts as a chromatin insulator to block enhancers that lie further 3' on the chromosome. Based on this model we would expect that enhancers of brain-specific expression of Igf2 would lie 5' of the ICR, and thus be insensitive to its action. Here we describe a 12 kb deletion of a region 5' of the ICR that is hypersensitive to nuclease digestion in chromatin. Its deletion results in a biallelic decrease in expression of Igf2, but not H19, in the brain, consistent with the proposal that it encodes a positive regulatory element. In addition, the deletion results in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue. Lastly, the reduction in IGFII expression in the adult is accompanied by increased fat deposition and occasional obesity. Overweight animals are hypophagic, suggesting that IGFII affects fat metabolism rather than feeding behavior in adult mice.
Hum Mol Genet 2001 Apr 01
PMID:Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity. 1128 46

Tumor necrosis factor (TNF)-alpha has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNF-RSF1B) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSF1B is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSF1B in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSF1B marker with CAD (chi2=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs. absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1-9.4, P<0.0001; in CA16 heterozygotes OR was 1.3, 95% CI 0.94-1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs. 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20-0.52, P<0.0001; in heterozygotes OR 0.41, 95% CI 0.26-0.63, P<0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0-1.9, P=0.027). Apolipoprotein A-I was elevated (P<0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1 +/- 0.1 ng/ml in CAD vs. 3.2 +/- 0.1 in control (P<0.0001), 5.2 +/- 0.1 in the presence vs. 4.6 +/- 0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2 +/- 0.2 (no angina), 5.0 +/- 0.1 (stable angina), 5.4 +/- 0.2 (unstable angina; P=0.003). sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor beta and homocysteine and was influenced by TNFRSF1B genotype. Thus genetic variation in or near the TNFRSF1B locus may predispose to CAD.
J Mol Med (Berl) 2001 Apr
PMID:Tumor necrosis factor receptor 2 gene (TNFRSF1B) in genetic basis of coronary artery disease. 1135 33

This study examined the effect a polymorphism (L162V) in the gene for peroxisome proliferator activated receptor (PPAR) alpha in the development of non-insulin-dependent diabetes mellitus (type 2 DM), obesity and hyperlipidaemia. The frequency of the L162V polymorphism in the PPARalpha gene was determined in 370 morbidly obese patients who underwent gastric banding surgery, 154 patients attending a type 2 DM clinic, 188 patients attending a lipid clinic and 199 healthy blood donors. The overall frequency of the V allele of the L162V polymorphism was 0.06. There were no significant differences in the allele frequency between patients with morbid obesity, hyperlipidaemia, type 2 DM and healthy controls, suggesting that it does not play a major role in the development of these conditions. The polymorphism was associated with a lower body mass index (BMI) in two independently recruited groups of patients with type 2 DM. There was no effect of the polymorphism on subjects without type 2 DM. Thus a polymorphism in PPARalpha protects type 2 DM patients from the overweight which is frequently associated with their condition.
J Mol Med (Berl) 2001 May
PMID:A polymorphism, L162V, in the peroxisome proliferator-activated receptor alpha (PPARalpha) gene is associated with lower body mass index in patients with non-insulin-dependent diabetes mellitus. 1140 11

Leptin is synthesized in adipocytes and acts primarily through central pathways suppressing appetite and increasing the metabolic rate in rodents as well as in humans. Recently leptin has also been suggested to have peripheral effects and be involved in insulin action. Since cytokines and chemokines may have effects on appetite regulation as well as on some of the obesity-related complications e.g. insulin resistance and cardiovascular disease, we investigated the effects of various cytokines and chemokines on leptin production in human adipose tissue fragments in vitro. Abdominal subcutaneous adipose tissue from healthy normal to overweight females was incubated for up to 48 h with the cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) and the chemokine: interleukin-8 (IL-8). IL-1beta (50 ng/ml) and TNF-alpha (10 ng/ml) decreased leptin production by 30-50% (P<0.05) and gene expression by 80-90% (P<0.05). In contrast, IL-6 and IL-8 had no effect on either leptin production or leptin gene expression. Interestingly, IL-1beta elicited a biphasic effect on leptin release with an incremental phase observed within 4 h with no concomitant change in leptin gene expression, followed by a long-lasting inhibition of leptin release and leptin gene expression. This could suggest that IL-1beta through a post-translational pathway induced an acute increase in leptin-secretion, perhaps through the release of leptin from a pre-formed pool within the adipose tissue. The long-term decrease in both leptin secretion and transcription could indicate that pro-inflammatory cytokines such as IL-1beta and TNF-alpha might influence the circulating leptin levels and thereby influence the adipose tissue to brain signalling, which could be of importance in relation to the obesity-associated diseases such as insulin resistance and cardiovascular disease.
Mol Cell Endocrinol 2002 Apr 25
PMID:Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro. 1199 82


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