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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated whether our previous reports of increased postmenopausal breast cancer risk with higher body mass index (BMI) or of reduced premenopausal and postmenopausal breast cancer risk with higher physical activity levels varied according to the tumor's estrogen receptor (ER) and progesterone receptor (PR) status. Participants enrolled in either of two population-based case-control studies in Los Angeles County, California: one of premenopausal women (ages < or = 40 years), and one of postmenopausal women (ages 55-64 years). Case participants were diagnosed for the first time with in situ or invasive breast cancer from 7/1/83 through 12/31/88 (premenopausal women) or from 3/1/87 through 12/31/89 (postmenopausal women). Joint ER/PR status was collected for 424 premenopausal and 760 postmenopausal case participants. The analysis included 714 premenopausal and 1091 postmenopausal age-matched, race-matched (white or Hispanic), parity-matched (premenopausal women only), and residential neighborhood-matched control participants. Among the postmenopausal women, obesity was associated with an increased odds of ER+/PR+ breast cancer (odds ratio, 2.45 for women in the highest versus the lowest body mass index quartile; 95% confidence interval, 1.73-3.47). Body mass index was associated with neither ER-/PR- tumors among the postmenopausal women nor with any ER/PR subgroup among the premenopausal women. For both premenopausal and postmenopausal women, higher recreational physical activity levels (> or = 17.6 MET-hours/week versus no activity) were associated with a 30-60% reduction in risk of nearly all ER/PR subtypes, although the associations were generally of borderline statistical significance. Examining these potentially modifiable breast cancer risk factors by tumor ER and PR status may provide us with greater insight into breast cancer etiology and the mechanisms underlying the risk factor associations.
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PMID:Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies. 1091 38

Soy protein is a major component of the diet of food-producing animals and is increasingly important in the human diet. However, soy protein is not an ideal protein because it is deficient in the essential amino acid methionine. Methionine supplementation benefits soy infant formulas, but apparently not food intended for adults with an adequate nitrogen intake. Soy protein content of another essential amino acid, lysine, although higher than that of wheat proteins, is still lower than that of the milk protein casein. Adverse nutritional and other effects following consumption of raw soybean meal have been attributed to the presence of endogenous inhibitors of digestive enzymes and lectins and to poor digestibility. To improve the nutritional quality of soy foods, inhibitors and lectins are generally inactivated by heat treatment or eliminated by fractionation during food processing. Although lectins are heat-labile, the inhibitors are more heat-stable than the lectins. Most commercially heated meals retain up to 20% of the Bowman-Birk (BBI) inhibitor of chymotrypsin and trypsin and the Kunitz inhibitor of trypsin (KTI). To enhance the value of soybeans in human nutrition and health, a better understanding is needed of the factors that impact the nutrition and health-promoting aspects of soy proteins. This paper discusses the composition in relation to properties of soy proteins. Also described are possible beneficial and adverse effects of soy-containing diets. The former include soy-induced lowering of cholesterol, anticarcinogenic effects of BBI, and protective effects against obesity, diabetes, irritants of the digestive tract, bone, and kidney diseases, whereas the latter include poor digestibility and allergy to soy proteins. Approaches to reduce the concentration of soybean inhibitors by rearrangement of protein disulfide bonds, immunoassays of inhibitors in processed soy foods and soybean germplasm, the roles of phytoestrogenic isoflavones and lectins, and research needs in all of these areas are also discussed. This integrated overview of the widely scattered literature emphasizes general concepts based on our own studies as well as recent studies by others. It is intended to stimulate interest in further research to optimize beneficial effects of soy proteins. The payoff will be healthier humans and improved animal feeds.
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PMID:Nutritional and health benefits of soy proteins. 1131 15

Hyperhomocysteinemia (HHcy) is a metabolic disorder frequently occurring in the elderly population. Recently several reports have suggested abnormalities in homocysteine (tHcy) metabolism implicating HHcy as a metabolic link in the multifactorial processes characterizing many geriatric illnesses-with special emphasis on atherosclerotic vascular diseases and cognitive impairment. The present study was undertaken in a large sample of elderly hospitalized subjects to determine (1) the prevalence of HHcy, (2) the association of HHcy with vascular and cognitive disorders, and (3) the factors independently predicting Hhcy. Six hundred elderly subjects (264 men and 336 women; mean age, 79 +/- 9 years) were randomly chosen from those admitted as inpatients over a period of 3 years. In all patients, body mass index (BMI), mid-upper arm muscle area (MUAMA), plasma cholesterol, triglycerides, total proteins, albumin, lymphocyte count, creatinine, homocysteine (fasting and 4 hours after methionine oral load), serum vitamin B(6), vitamin B(12), and folate concentrations were measured. The presence of disease or use of medications known to affect homocysteine plasma levels were also recorded. The mean fasting tHcy level was 16.8 +/- 12 micromol/L in the whole sample, 18.18 +/- 13.25 micromol/L in men, and 15.86 +/- 12.14 micromol/L in women (P =.005 men v women). The mean Hcy level 4 hours after methionine load was 37.95 +/- 20.9 in the whole sample. Prevalence of hyperhomocysteinemia (fasting Hcy > or = 15 micromol/L or 4 hours after methionine load > or = 35 micromol/L) was 61% (365/600) (67% in men and 56% in women, P <.05). HHcy was rarely (8%) an isolated disorder; in addition to diabetes (20%), renal failure (48.2%), and malnutrition (20.2%), it was often associated with heart failure (30%), malignancies (20.5%), and the use of diuretics (56%) and anticonvulsant drugs (13%). Plasma homocysteine progressively increases across subjects from those with no diabetes, malnutrition, renal failure, obesity, inflammatory bowel disease, heart failure to those with 1, 2, or more concurrent diseases. Multiple stepwise regression analysis showed that 72% of plasma total fasting tHcy variability was explained by age, serum folate, plasma albumin, use of diuretics, and renal function (measured as plasma creatinine clearance). In conclusion, the present study documents that hyperhomocysteinemia, in elderly hospitalized patients is (1) a common finding, (2) frequently associated with vascular and cognitive disorders, and (3) probably a secondary phenomenon in most cases. The major predictor of high plasma homocysteine levels were age, serum folate, plasma albumin, plasma creatinine clearance, and use of diuretic drugs. These variables explain a large proportion of plasma Hcy variability.
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PMID:Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects. 1173 95

A simple and convenient high performance liquid chromatographic method with UV detection is described for the determination of mazindol [5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol] and its major metabolite, 2-(2-aminoethyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidine (Met), in human plasma. The analytes were extracted with ethyl acetate from plasma samples and separated on a C18 column using acetonitrile-0.067 mol dm(-3) phosphate buffer (pH 3.5) (24 + 76 v/v) as a mobile phase. The eluates were monitored at 220 nm. Following complete validation and stability studies, the proposed method proved to be sensitive and precise. The limits of detection were 0.07 and 0.08 ng ml(-1) of plasma for mazindol and Met, respectively. The accuracy and recovery were in the ranges 94-102% and 91-102%, respectively, for both compounds. The intra- and inter-assay precisions were less than 7.6 and 9.2%, respectively, for both compounds. The stability of mazindol under different storage conditions, i.e., at room temperature (rt) and 4 degrees C and with freeze-thaw cycles, was also examined. Mazindol was unstable in plasma samples left at rt and 4 degrees C. The method was applied to the determination of mazindol and Met in the plasma of a patient treated for obesity with mazindol.
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PMID:High performance liquid chromatographic determination of mazindol in human plasma. 1176 75

Ghrelin induces obesity via central and peripheral mechanisms. Administration of ghrelin leads to increased food intake and decreased fat utilisation in rodents. Ghrelin levels are decreased in obese individuals. Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity. We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP). We found the two previously described single nucleotide polymorphisms (SNP: Arg-51-Gln and Leu-72-Met) in similar frequencies in study groups 1 and 2 (allele frequencies were: 0.019 and 0.016 for the 51-Gln allele and 0.091 and 0.086 for the 72-Met allele, respectively). Hence, we could not confirm the previous finding. Additionally, two novel variants were identified within the coding region: (1) We detected one healthy normal weight individual with a frameshift mutation (2bp deletion at codon 34). This frameshift mutation affects the coding region of the mature ghrelin. Hence, it is highly likely that the normal weight student is haplo-insufficient for ghrelin. (2) An A to T transversion leads to an amino acid exchange from Gln to Leu at amino acid position 90. The frequency of the 90-Leu allele was significantly higher in the extremely obese children and adolescents (0.063) than in the normal weight students (0.016; nominal p = 0.011). Additionally, we genotyped 134 underweight students and 44 normal weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students and normal weight adults (p > 0.8). In conclusion, we identified four sequence variants in the coding region of the ghrelin gene in individuals belonging to different weight extremes. A frameshift mutation was detected in a normal weight individual. None of the variants seem to influence weight regulation.
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PMID:Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students. 1205 Feb 39

In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
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PMID:Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. 1206 Jun 74

Carnitine acyltransferases catalyze the exchange of acyl groups between coenzyme A (CoA) and carnitine. They have important roles in many cellular processes, especially the oxidation of long-chain fatty acids, and are attractive targets for drug discovery against diabetes and obesity. These enzymes are classified based on their substrate selectivity for short-chain, medium-chain, or long-chain fatty acids. Structural information on carnitine acetyltransferase suggests that residues Met-564 and Phe-565 may be important determinants of substrate selectivity with the side chain of Met-564 located in the putative binding pocket for acyl groups. Both residues are replaced by glycine in carnitine palmitoyltransferases. To assess the functional relevance of this structural observation, we have replaced these two residues with small amino acids by mutagenesis, characterized the substrate preference of the mutants, and determined the crystal structures of two of these mutants. Kinetic studies confirm that the M564G or M564A mutation is sufficient to increase the activity of the enzyme toward medium-chain substrates with hexanoyl-CoA being the preferred substrate for the M564G mutant. The crystal structures of the M564G mutant, both alone and in complex with carnitine, reveal a deep binding pocket that can accommodate the larger acyl group. We have determined the crystal structure of the F565A mutant in a ternary complex with both the carnitine and CoA substrates at a 1.8-A resolution. The F565A mutation has minor effects on the structure or the substrate preference of the enzyme.
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PMID:Structural and biochemical studies of the substrate selectivity of carnitine acetyltransferase. 1515 26

Poor development in utero may favor the development of obesity in adulthood. Animal studies showed that embryo manipulation in vitro or nutritional insults during the embryonic and fetal stages of development may lead to obesity in adult life. We studied the in vitro proliferation and differentiation of adipocytes to investigate whether early protein restriction may program cell growth and development. In a series of experiments, 2 different low-protein diet protocols were compared. In both cases, pregnant rats were fed a diet with a high (18-20%) or low (8-9%) protein content during gestation and/or lactation. Preadipocytes were isolated from the fetuses, neonates, and weanling offspring. Moderate protein restriction, imposed during either gestation and/or lactation, did not affect the capacity of preadipose cells to divide or store fat. Because previous studies showed that early protein restriction alters the metabolism of sulfur amino acids, we also investigated the effects of methionine, taurine, and homocysteine on proliferation and differentiation of preadipocytes. The supplementation of the diet with methionine or the addition of homocysteine and taurine to the culture media did not influence the development of preadipocytes. We obtained no evidence for the direct reprogramming of the precursor or stem cells and suggest that the subsequent alteration in fat accretion may therefore reflect a change in the neuroendocrine environment.
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PMID:Prenatal protein restriction does not affect the proliferation and differentiation of rat preadipocytes. 1517 17

The incidence of colon cancer is high in many developed nations, especially New Zealand. Molecular understanding of the nature of colon cancer shows a disease whose well-characterized morphological progression is paralleled at the cellular level by increased numbers of gene or chromosome mutations, loss of heterozygosity, changed methylation patterns, and genomic instability. In the present study, we consider whether an imbalance of factors that affect DNA methylation patterns might explain at least part of the high colon cancer incidence in New Zealand. Folate is the major micronutrient whose intake impacts methylation, particularly through interaction with choline and methionine. Folate is generally somewhat deficient in the New Zealand diet, with the voluntary addition of folate to white flour not producing desired levels. Selenium affects methylation status in several ways and is recognized as being low in New Zealand soils and, therefore, diet. Zinc is also low in the diets of some New Zealand population groups, which can lead to hypomethylation. Several of the components of fruits and vegetables affect methylation patterns, and the average New Zealand intake, at two to three servings per day, is considerably below recommended amounts. Low dietary fiber, high tobacco use, and increasing rates of obesity are also likely New Zealand risk factors that may impact on methylation status. Dietary supplementation is not as common in New Zealand as in countries such as the United States, but may provide a way to raise the levels of nutrients and phytochemicals affecting methylation status, thereby enhancing colon cancer protection.
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PMID:Epigenetic events and protection from colon cancer in New Zealand. 1519 45

Mitochondrial generation of reactive oxygen species (ROS) is increased in mice with fatty livers induced by genetic obesity, chronic consumption of ethanol, or methionine/choline-deficient diets. Both nuclear and mitochondrial (mt) DNA are targets for ROS-induced damage and accumulate hydroxylated bases, such as 8-hydroxy-2'-deoxyguanosine (8-oxoG) and base substitution of adenine with 8-oxoG (A*8-oxoG), that introduce mutations that promote cancer as well as cell death. The mammalian homolog of the bacterial DNA mismatch repair enzyme MutY (MYH) removes A*8-oxoG from nuclear and mtDNA, reduces 8-oxoG accumulation, and restores genomic stability after ROS exposure. Cumulative damage to mtDNA occurs as fatty liver disease progresses. Therefore, differences in hepatic MYH activity may influence the severity of fatty liver disease. To evaluate this hypothesis, we compared mtH2O2 production, MYH expression, oxidative DNA damage, and hepatocyte death in healthy mice and different mouse models of fatty liver disease. The results show that diverse causes of steatohepatitis increase mtROS production, limit repair of mtDNA, and oxidatively damage DNA. However, there are important differences in the DNA repair response to oxidant stress among mouse models of fatty liver disease. Independent of the degree of mtROS generation, models with the least MYH exhibit the greatest accumulation of 8-oxoG and the most hepatocyte death. These findings raise the intriguing possibility that inherited or acquired differences in DNA repair enzyme activity may underlie some of the interindividual differences in fatty liver disease outcomes.
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PMID:Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. 1523 85


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