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

1. Recent molecular genetic studies have implicated the low-density-lipoprotein receptor gene locus (LDLR, at chromosome 19p13.2) in obesity in essential hypertensive patients and in the atherogenic lipoprotein phenotype. The present study examined genotypes for the obesity-associated ApaLI restriction fragment length polymorphism of LDLR, and genotypes for a hypertension-associated RsaI restriction fragment length polymorphism at the insulin receptor gene (INSR) locus, which is linked to LDLR, in relation to plasma lipids, body mass index and blood pressure in 27 obese and 57 non-obese Caucasians with severe essential hypertension, selected on the basis of having parents who were both hypertensive, and in 25 obese and 45 non-obese normotensive subjects selected on the basis of having parents who were both normotensive after the age of 50 years. 2. Plasma triacylglycerol and low-density-lipoprotein-cholesterol were elevated in hypertensive patients, but did not differ between the obese and non-obese hypertensive groups. Significant positive correlations were seen between body mass index and triacylglycerol and low-density-lipoprotein-cholesterol in the obese and non-obese hypertensive patients, respectively. In addition, obese hypertensive patients had significantly higher diastolic blood pressure than non-obese hypertensive patients. 3. The eight obese hypertensive patients who were homozygous for the obesity-associated 6.6 kb allele of the ApaLI restriction fragment length polymorphism of LDLR ('6.6. kb homozygotes') had a significantly higher body mass index [34 +/- 6.0 (SD) kg/m2] than the 18 heterozygotes (29 +/- 2.7 kg/m2) and the single subject who was homozygous for the 9.4 kb allele (29 kg/m2) (P = 0.012 by one-way analysis of variance). The body mass index of the eight hypertensive 6.6 kb homozygotes was also greater than the body mass index of 29 +/- 2.4 kg/m2 observed for the eight obese normotensive 6.6 kb homozygotes. In addition, the eight obese hypertensive 6.6 kb homozygotes had a higher plasma triacylglycerol [4.2 +/- 0.77 (SEM) mmol/l] than the 18 obese hypertensive heterozygotes (2.4 +/- 0.33 mmol/l; P = 0.045). Non-obese hypertensive patients showed no significant genotypic differences in relation to the LDLR restriction fragment length polymorphism. 4. In the normotensive group, however, the frequency of the 6.6 kb allele of the LDLR ApaLI restriction fragment length polymorphism in obese subjects (0.54) was not significantly greater than in non-obese subjects (0.48) [cf. the significantly (P = 0.004( different values of 0.63 and 0.39, respectively, in obese and non-obese hypertensive patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Significant relationships of plasma lipids and body mass index with polymorphisms at the linked low-density-lipoprotein receptor gene and insulin receptor gene loci (19p13.2) in essential hypertensive patients. 803 1

Vascular calcification is common in people with diabetes and its presence predicts premature mortality. To clarify the underlying mechanisms, we used low density lipoprotein receptor-deficient (LDLR -/-) mice to study vascular calcification in the ascending aorta. LDLR -/- mice on a chow diet did not develop obesity, diabetes, atheroma, or vascular calcification. In contrast, LDLR -/- mice on high fat diets containing cholesterol developed obesity, severe hyperlipidemia, hyperinsulinemic diabetes, and aortic atheroma. A high fat diet without cholesterol also induced obesity and diabetes, but caused only moderate hyperlipidemia and did not result in significant aortic atheroma formation. Regardless of cholesterol content, high fat diets induced mineralization of the proximal aorta (assessed by von Kossa staining) and promoted aortic expression of Msx2 and Msx1, genes encoding homeodomain transcription factors that regulate mineralization and osseous differentiation programs in the developing skull. Osteopontin (Opn), an osteoblast matrix protein gene also expressed by activated macrophages, was up-regulated in the aorta by these high fat diets. In situ hybridization showed that peri-aortic adventitial cells in high fat-fed mice express Msx2. Opn was also detected in this adventitial cell population, but in addition was expressed by aortic vascular smooth muscle cells and macrophages of the intimal atheroma. High fat diets associated with hyperinsulinemic diabetes activate an aortic osteoblast transcriptional regulatory program that is independent of intimal atheroma formation. The spatial pattern of Msx2 and Opn gene expression strongly suggests that vascular calcification, thought to be limited to the media, is an active process that can originate from an osteoprogenitor cell population in the adventitia.
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PMID:Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. 980 9

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of genetic susceptibility' and risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (ε4) and decrease (ε2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1--C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. (ABSTRACT TRUNCATED)
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PMID:Ionizing radiation and genetic risks. VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease, essential hypertension and diabetes mellitus. 987 81

The aim of this study was to determine whether phenotypes associated with type 2 diabetes are altered in dyslipidemic obese mice. C57BL/6 wild-type, low-density lipoprotein (LDL) receptor-deficient (LDLR-/-), and apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat, high-carbohydrate diet (diabetogenic diet), and the development of obesity, diabetes, and hypertriglyceridemia was examined. Wild-type mice became obese and developed hyperglycemia, but not hypertriglyceridemia, in response to this diet. LDLR-/- mice fed the diabetogenic diet became more obese than wild-type mice and developed severe hypertriglyceridemia and hyperleptinemia. Surprisingly, glucose levels were only modestly higher and insulin levels and insulin-to-glucose ratios were not strikingly different from those of wild-type mice. In contrast, diabetogenic diet-fed apoE-/- mice were resistant to changes in glucose and lipid homeostasis despite becoming obese. These data suggest that modifications in lipoprotein profiles associated with loss of the LDL receptor or apoE function have profound and unique consequences on susceptibility to diet-induced obesity and type 2 diabetic phenotypes.
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PMID:LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice. 1173 2

We investigated whether fenofibrate improves lipid metabolism and obesity in female ovariectomized (OVX) or sham-operated (SO) low density lipoprotein receptor-null (LDLR-null) mice. All mice fed a high-fat diet exhibited increases in serum triglycerides and cholesterol as well as in body weight and white adipose tissue (WAT) mass compared to mice fed a low fat control diet. However, fenofibrate prevented high-fat diet-induced increases in body weight and WAT mass in female OVX LDLR-null mice, but not in SO mice. In addition, administration of fenofibrate reduced serum lipids and hepatic apolipoprotein C-III mRNA while increasing the mRNA of acyl-CoA oxidase in both groups of mice, however, these effects were more pronounced in OVX LDLR-null mice. The results of this study provide first evidence that fenofibrate improves both lipid metabolism and obesity, in part through PPARalpha activation, in female OVX LDLR-null mice.
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PMID:Fenofibrate improves lipid metabolism and obesity in ovariectomized LDL receptor-null mice. 1259 43

The aims of this study were to determine whether mice induced to become obese also exhibited accelerated atherosclerosis, and to determine whether obesity itself or dyslipidemia associated with obesity enhanced atherosclerosis. Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR-/-) or apolipoprotein E (apoE-/-) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity. As compared with wild-type mice, diabetogenic diet-fed LDLR-/- mice became more obese and developed severe dyslipidemia. Consequently, atherosclerotic lesions were increased in the LDLR-/- mice 3.7-fold over chow fed values. ApoE-/- mice showed weight gain profiles similar to those observed for wild-type mice. However, no differences in plasma lipid levels, lipoprotein profiles or atherosclerotic lesion areas were observed between chow-fed and diabetogenic diet-fed apoE-/- mice. These data demonstrate that lipid storage and partitioning as mediated by the low density lipoproteins (LDL) receptor or apoE-/- have profound and opposing consequences for dyslipidemia and atherosclerosis susceptibility associated with obesity.
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PMID:Mice deficient in apolipoprotein E but not LDL receptors are resistant to accelerated atherosclerosis associated with obesity. 1464 5

Our previous study demonstrated that fenofibrate improves both lipid metabolism and obesity, in part through hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) activation, in female ovariectomized, but not in sham-operated, low-density lipoprotein receptor-null (LDLR-null) mice. The aim of this study was to determine whether fenofibrate prevents obesity and hypertriglyceridemia in male LDLR-null mice. Mice fed a high-fat diet for 8 weeks exhibited increases in body and white adipose tissue (WAT) weights and developed severe hypertriglyceridemia compared with mice fed a low-fat control diet. However, these effects were effectively prevented by fenofibrate. Mice given a fenofibrate-supplemented high-fat diet showed significantly reduced body weight, WAT weight, and serum triglycerides versus high-fat diet-fed animals. Triton WR1339 study showed that fenofibrate-induced reduction in circulating triglycerides was due to the decreased secretion of triglycerides from the liver. Moreover, the administration of fenofibrate not only resulted in liver hypertrophy and reduction in hepatic lipid accumulation, but also regulated the transcriptional expression of PPARalpha target genes, such as hepatic acyl-coenzyme A (CoA) oxidase and apolipoprotein C-III (apoC-III). Therefore, our results suggest that alterations in hepatic PPARalpha action by fenofibrate seem to suppress diet-induced obesity and severe hypertriglyceridemia caused by LDLR deficiency in male mice.
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PMID:Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice. 1513 65

Despite a clear association between obesity, insulin resistance and atherosclerosis in humans, to date, no animal models have been described in which insulin resistance is associated with atherosclerotic lesion burden. Using two mouse models of obesity-induced hyperlipidemia:leptin deficient (ob/ob) mice on an apolipoprotein E deficient (apoE-/-) or low density lipoprotein receptor deficient (LDLR-/-) background, we sought to determine metabolic parameters most closely associated with atherosclerotic lesion burden. Total plasma cholesterol (TC) levels in ob/ob;apoE-/- mice and ob/ob;LDLR-/- mice were indistinguishable (682+/-48 versus 663+/-16, respectively). Analysis of lipoprotein profiles showed that cholesterol was carried primarily on VLDL in the ob/ob;apoE-/- mice and on LDL in the ob/ob;LDLR-/- mice. Plasma triglycerides (TG) were 55% lower (P<0.001), non-esterified fatty acids (NEFA) were 1.5-fold higher (P<0.01), and insulin levels were 1.7-fold higher (NS) in ob/ob;apoE-/- mice compared to ob/ob;LDLR-/- mice. Other parameters such as body weight, fat pad weight, and glucose levels were not different between the groups. Aortic sinus lesion area of ob/ob;apoE-/- mice was increased 3.2-fold above ob/ob;LDLR-/- mice (102,455+/-8565 microm2/section versus 31,750+/-4478 microm2/section, P<0.001). Lesions in ob/ob;apoE-/- mice were also more complex as evidenced by a 7.7-fold increase in collagen content (P<0.001). Atherosclerotic lesion area was positively correlated with body weight (P<0.005), NEFA (P=0.007), and insulin (P=0.002) levels in the ob/ob;LDLR-/- mice and with insulin (P=0.014) in the ob/ob;apoE-/- mice. In contrast, lesion burden was neither associated with TC and TG, nor with individual lipoprotein pools, in either animal model. These data provide a direct demonstration of the pathophysiologic relevance of hyperinsulinemia, NEFA, and increased body weight to atherosclerotic lesion formation.
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PMID:Plasma insulin levels predict atherosclerotic lesion burden in obese hyperlipidemic mice. 1610 72

Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or A at position -463, and crossed these to the LDL receptor-deficient (LDLR(-/-)) mouse. The -463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high-fat-fed LDLR(-/-) mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR(-/-) males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and MPOA-expressing LDLR(-/-) males also exhibited significantly larger aortic lesions than control LDLR(-/-) males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.
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PMID:Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males. 1663 78

Vitamin E is a natural antioxidant that has been used in animal and human studies to determine its potential in reducing cardiovascular risk; however, a detailed study in an established obese model of atherosclerosis has yet to be performed. In our current study, we show that obesity and hyperlipidemia cause a synergistic, age-related increase in urinary isoprostane levels in mice deficient in both leptin and low-density lipoprotein receptor (ob/ob;LDLR-/-). Based upon this observation, we hypothesized that vitamin E supplementation would induce potent antiatherogenic effects in this model. Lean and obese LDLR-/- mice were provided vitamin E (2000 IU/kg) in a Western-type high-fat diet for 12 weeks. Plasma lipid parameters, such as total cholesterol (TC), triglyceride (TG) and free fatty acid, were significantly higher in obese mice compared to lean mice at baseline (P<.001). Western-type diet (WD) feeding caused an increase in TC levels in all groups (P<.001); however, TG (P<.001) and free fatty acid (P<.01) were elevated only in lean mice following WD feeding. Vitamin E supplementation neither influenced any of these parameters nor reduced urinary isoprostanes in lean or obese mice. Vitamin E supplementation in ob/ob;LDLR-/- mice resulted in a trend toward a reduction in atherosclerotic lesion area (P=.10), although no differences in lesion area were noted in lean LDLR-/- animals. These data provide evidence that vitamin E supplementation is not sufficient to reduce extreme elevations in systemic oxidative stress due to hyperlipidemia and obesity and, thus, may not be cardioprotective in this setting.
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PMID:Effects of vitamin E on oxidative stress and atherosclerosis in an obese hyperlipidemic mouse model. 1678 57


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