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

In male rats, genetic obesity and experimental diabetes are associated with altered activities of several of the hepatic microsomal P-450 isozymes concerned with steroid and xenobiotic oxidation. The present study examined the roles of insulin and ketonaemia in effecting these changes. In obese male Zucker rats, androstenedione 6 beta-, 16 alpha- and 16 beta-hydroxylase activities (mediated by P450PCN-E, P-450UT-A and P450PB-B, respectively) were significantly decreased to 21%, 20% and 43% of lean control. Obesity was also associated with a significant decrease in the activities of N-nitrosodimethylamine demethylase (P-450j) and aniline p-hydroxylase to about 70%. A similar decrease in total microsomal P-450 was also observed. Androstenedione 7 alpha-hydroxylase activity (mediated by P-450UT-F) was unchanged in these animals. In streptozotocin-induced diabetic male Wistar rats, androstenedione 7 alpha- and 16 beta-hydroxylase activities were significantly elevated to 230% and 270% of control, respectively. Significant increases in the rates of N-nitrosodimethylamine demethylase and aniline p-hydroxylase were also noted in diabetic rat liver. In contrast, the activity of P-450UT-A was reduced to 30% of control and P-450PCN-E-specific 6 beta-hydroxylation was unchanged. Control of the diabetic state with insulin treatment reversed all the changes in P-450-mediated activities. Significant correlations were found between serum concentrations of insulin and catalytic activities of P-450PB-B (rho = -0.46), P-450UT-F (rho = -0.65) and P-450j (rho = -0.71). Positive correlations of the same magnitude were also found between these mixed function oxidase activities and beta-hydroxybutyrate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of genetic obesity and experimental diabetes on hepatic microsomal mixed function oxidase activities. 210 7

The mechanism for enhanced metabolism of inhaled anesthetics in obese rats and humans is unknown. In this study, hepatic microsomes from normal-weight chow-fed rats and rats fed a high fat diet for approximately 54 weeks to induce obesity were examined for their ability to metabolize fluorinated inhalation anesthetics. Body composition of rats on diet for 54 weeks revealed a significantly elevated lipid content of both the whole body and liver in obese compared to normal-weight rats. Protein per g liver was not significantly different. The hepatic microsomal content of cytochromes b5 and P-450 per mg protein was not different between obese and normal-weight rats. Hepatic microsomal defluorination rates of the anesthetics, methoxyflurane, enflurane and isoflurane, were not altered by high fat diets of 54 weeks duration. The activity rate of aminopyrine N-demethylase was not changed by the diet; however, p-nitroanisole O-demethylase activity was significantly increased in microsomes from obese rats to approximately 150% of control activity. Thus the enhanced in vivo anesthetic metabolism of obese Fischer 344 rats does not appear to be the result of an increase in the specific activity of anesthetic metabolizing enzymes.
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PMID:In vitro hepatic drug and anesthetic metabolism of rats with dietary-induced obesity. 277 69

The hepatic expression of xenobiotic-metabolising cytochrome P450 isoforms in the genetically obese Zucker rat, a model of obesity, was compared to that of its lean littermate. Cytochrome P450 (CYP) levels were determined using diagnostic substrates and/or immunologically in Western blot analyses. When compared with the lean Zucker rat, the obese animal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperinsulinaemia and hypertriglyceridaemia but was normoketonaemic. CYP3A and CYP1A2 levels were higher in the obese Zucker rat when compared with the lean littermate but, in contrast, a protein recognised by human CYP2D6 and, to a lesser extent, CYP2C11 levels were lower. Pretreatment with acetone, dexamethasone and clofibrate resulted in enhanced p-nitrophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and lauric acid hydroxylase (CYP4A) activities respectively in the liver of the lean Zucker rat but, in contrast, the obese Zucker rat was refractive to such treatment; similarly, hepatic apoprotein levels of the CYP2E and CYP4A subfamilies were increased markedly only in the lean Zucker rat. It is concluded that CYP2E, CYP3A and CYP4A subfamilies are poorly expressed in the obese Zucker rat, and this rat strain may serve as a good model for elucidating the molecular mechanisms of induction of these cytochrome P450 proteins.
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PMID:Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat. 874 92

Variants in the FTO (oxoglutarate-dependent nucleic acid demethylase) gene have been associated with the BMI determination in Western European and North American populations. To widen the geographical coverage of the FTO studies, we have analyzed the association between the FTO gene variant rs17817449 (G>C) and obesity in a Slavic Eastern European population. A total of 3,079 males and 3,602 females 45-69 years old were randomly selected from population registers of seven Czech cities. We examined three indices of obesity: BMI (kg/m(2)), waist circumference, and waist-to-hip ratio (WHR). The FTO rs17817449 variant was significantly associated with BMI both in males (GG 28.7 +/- 4.1; GT 28.3 +/- 3.9; TT 28.0 +/- 3.9; P = 0.003) and females (GG 28.7 +/- 5.2; GT 28.2 +/- 5.1; TT 27.2 +/- 4.9; P < 0.001); the associations were not affected by adjustment for age, smoking, socioeconomic status, and physical activity. The FTO variant was also associated with waist circumference (difference between GG and TT was 1.1 cm (P = 0.043) in men and 2.4 cm (P < 0.001) in women) but this relationship disappeared after adjustment for BMI. Similarly, BMI explained the weak association of FTO with WHR and C-reactive protein. FTO was not associated with plasma total and high-density lipoprotein cholesterol, triglycerides, blood glucose, and blood pressure. These results confirm that in a Slavic population the FTO variant is strongly associated with BMI but not with other risk factors.
Obesity (Silver Spring) 2008 Dec
PMID:The FTO gene and obesity in a large Eastern European population sample: the HAPIEE study. 1883 10

Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.
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PMID:Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. 1919 61

Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and alpha-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a-/-) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a-/- mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.
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PMID:Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. 1962 51

Recent studies have unequivocally associated the fat mass and obesity-associated (FTO) gene with the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA. Here we report the crystal structure of FTO in complex with the mononucleotide 3-meT. FTO comprises an amino-terminal AlkB-like domain and a carboxy-terminal domain with a novel fold. Biochemical assays show that these two domains interact with each other, which is required for FTO catalytic activity. In contrast with the structures of other AlkB members, FTO possesses an extra loop covering one side of the conserved jelly-roll motif. Structural comparison shows that this loop selectively competes with the unmethylated strand of the DNA duplex for binding to FTO, suggesting that it has an important role in FTO selection against double-stranded nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from other nucleotides is conferred by its hydrogen-bonding interaction with the two carbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these results provide a structural basis for understanding FTO substrate-specificity, and serve as a foundation for the rational design of FTO inhibitors.
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PMID:Crystal structure of the FTO protein reveals basis for its substrate specificity. 2037 3

The fat mass and obesity associated, FTO, gene has been shown to be associated with obesity in human in several genome-wide association scans. In vitro studies suggest that Fto may function as a single-stranded DNA demethylase. In addition, homologous recombination-targeted knockout of Fto in mice resulted in growth retardation, loss of white adipose tissue, and increase energy metabolism and systemic sympathetic activation. Despite these intense investigations, the exact function of Fto remains unclear. We show here that Fto is a transcriptional coactivator that enhances the transactivation potential of the CCAAT/enhancer binding proteins (C/EBPs) from unmethylated as well as methylation-inhibited gene promoters. Fto also exhibits nuclease activity. We showed further that Fto enhances the binding C/EBP to unmethylated and methylated DNA. The coactivator role of FTO in modulating the transcriptional regulation of adipogenesis by C/EBPs is consistent with the temporal progressive loss of adipose tissue in the Fto-deficient mice, thus suggesting a role for Fto in the epigenetic regulation of the development and maintenance of fat tissue. How FTO reactivates transcription from methyl-repressed gene needs to be further investigated.
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PMID:The obesity-associated Fto gene is a transcriptional coactivator. 2085 58

Recent studies have unequivocally established the link between FTO and obesity. FTO was biochemically shown to belong to the AlkB-like family DNA/RNA demethylase. However, FTO differs from other AlkB members in that it has unique substrate specificity and contains an extended C-terminus with unknown functions. Insight into the substrate selection mechanism and a functional clue to the C-terminus of FTO were gained from recent structural and biochemical studies. These data would be valuable to design FTO-specific inhibitors that can be potentially translated into therapeutic agents for treatment of obesity or obesity-related diseases.
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PMID:A loop matters for FTO substrate selection. 2120 33

A single nucleotide polymorphism in the FTO gene is associated with obesity in humans. Evidence gathered in animals mainly relates energy homeostasis to the central FTO mRNA levels, but our knowledge of the Fto protein distribution and regulation is limited. Fto, a demethylase and transcriptional coactivator, is thought to regulate expression of other genes. Herein, we examined Fto immunoreactivity (IR) in the mouse and rat brain with emphasis on sites governing energy balance. We also studied whether energy status affects central Fto IR. We report that Fto IR, limited to nuclear profiles, is widespread in the brain, in- and outside feeding circuits; it shows a very similar distribution in feeding-related sites in mice and rats. Several areas regulating energy homeostasis display enhanced intensity of Fto staining: the arcuate, paraventricular, supraoptic, dorsomedial, ventromedial nuclei, and dorsal vagal complex. Some regions mediating feeding reward, including the bed nucleus of the stria terminalis, have ample Fto IR. We found that differences in energy status between rats fed ad libitum, deprived or refed following deprivation, did not affect the number of Fto-positive nuclei in 10 sites governing consumption for energy or reward. We conclude that Fto IR, widespread in the rodent brain, is particularly abundant in feeding circuits, but the number of Fto-positive neurons is unaffected by changes in energy balance.
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PMID:Fto immunoreactivity is widespread in the rodent brain and abundant in feeding-related sites, but the number of Fto-positive cells is not affected by changes in energy balance. 2129 49


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