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

Recently published results revealed linkage of obesity traits to a chromosomal region near the leptin receptor gene (Lepr) locus in high body weight selected big and fat DU6i mice. The purpose of this study was the search for variants of the Lepr gene in selected and unselected mouse lines as a candidate for different body composition traits. The complete Lepr cDNA sequence was analysed in DU6i mice. In addition, body weight, abdominal fat weight and serum leptin levels were measured in 42 day old, male mice of the strains DU6i, DUKs, Him : OF1 and DBA/2. Sequence comparison to the published wild type sequence revealed three silent mutations and an amino acid exchange (I359 V) in the C2 domain of the putative leptin binding site in the line DU6i. Compared to the high body weight selected mice also unselected lean control DUKs mice and Him : OF1 mice harbour the amino acid substitution, although they show significantly lower values for body weight, abdominal fat weight and serum leptin levels. Therefore, we assume that the mutation in the C2 domain of Lepr alone might not result in impaired leptin binding or signaling.
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PMID:A novel leptin receptor variant with a conservative amino acid substitution (I359 V) in body weight selected and unselected mouse lines. 1295 35

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.
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PMID:Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. 1467 Sep 88

To identify new genetic determinants relevant to type 2 diabetes (T2D), diabetic F2 progeny were generated by intercrossing F1 mice obtained from a cross of BKS.Cg-Lepr(db)+/+m and DBA/2, and T2D-related phenotypes were measured. In the F2 population, increased susceptibility to diabetes and obesity was observed. We also detected the major quantitative trait loci (QTL) modifying the severity of diabetes on chromosome 9, where peaks of logarithm of odds (LOD) overlapped for three traits. To identify candidate genes in the QTL intervals, we combined "expression QTL" (eQTL), taking mRNA levels as quantitative traits, and "interstrain sequence variations, including cSNPs." As a result, four genes were identified from cosegregation of clinical QTL with eQTL and 13 genes were found from interstrain cSNPs as candidates in the T2D modifier QTL. Our combined approach shows the acceleration of the discovery of candidate genes in the QTL of interest, spanning several megabases.
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PMID:Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. 1582 Mar 11

Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.
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PMID:High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction. 1608 20

Most quantitative trait loci (QTL) studies have focused on detecting the genetic effects of individual QTLs. This study thoroughly dissected the genetic components of type 2 diabetic mice, including a search for epistatic interactions and multi-locus additive effects that result in variation in diabetes-related phenotypes. F2 population was generated from BKS.Cg-Leprdb+/+m and DBA/2 intercross and separated into six subpopulations by sex and the db-dependent diabetes severity. Single-locus and pairwise genome scans first identified the QTLs in these F2 subpopulations, and next covariate-dependent scans confirmed their sex-, db- and sex-by-db-specific effects in the combined populations. Single-locus genome scans detected four QTLs (QBIS1, QBIS2, QBIS3 and QBIS4) that presented their genetic effects beyond sex, but most QTLs showed their effects specifically in limited conditions. This highly conditional feature of the QTLs was accentuated in the pairwise analysis. The pairwise genome scans uncovered a total of 27 significantly interacting or additively acting pairs of loci, showing a better fit to explain the total phenotypic variation of the traits. These significant pairs affected the traits under constantly varying combinations of loci in a time series or in both sexes. In addition, pairwise analysis indicated the appropriate genetic background in constructing congenic strains to obtain the maximum power in the replication of phenotypes. Our study showed high degree of complexity in the genetics of type 2 diabetes in mice, and it suggested that a comprehensive understanding of the multi-locus effects was essential to disentangle the complex genetics of diabetes and obesity in humans.
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PMID:Multidimensional genome scans identify the combinations of genetic loci linked to diabetes-related phenotypes in mice. 1632 90

The feeding response following administration of the anti-metabolic glucose analogue, 2-deoxy-d-glucose (2DG), is conceptualized as an experimental model of glucoprivation, which may contribute to the understanding of inter-individual differences in glucose and carbohydrate intake and, ultimately, obesity. Although variation in the intake of several nutrients as well as food and water are known to be associated with genetic variation, it is not known whether 2DG-induced feeding is similarly genotype dependent. The present study therefore examined 2DG-induced feeding in mice of 11 inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL6/J, C57BL10/J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) strains across a wide range of previously determined effective 2-DG doses (200, 400, 600, 800 mg/kg) and test times (1-4 h). Orderly dose-dependent increases in 2DG-induced feeding occurred after all four doses in outbred CD-1 and inbred DBA/2J mice, across the three highest doses for BALB/cJ, SJL/J and 129P3/J mice, and across the two highest doses for CBA/J and AKR/J mice. Limited instances of 2DG-induced feeding were noted only at the highest dose in A/J and C3H/HeJ mice, or at a moderate dose in C57BL/6J mice. Further, the full 2DG dose range failed to alter food intake in C57BL/10J mice, and produced significant reductions in food intake in SWR/J mice. Food intake after 2DG doses of 200-600 mg/kg, but not 800 mg/kg, displayed significant cross-correlation, suggesting that large 2DG doses may recruit non-specific effects upon food intake. There was no correlation between food intake in the absence (vehicle baseline) of and presence of 2DG, suggesting that the regulation of glucose intake in non-challenged mice does not predict subsequent responses to glucoprivic challenge. The data demonstrate genotype-dependent variability in this glucoprivic response, and may provide the basis for the subsequent identification of trait-relevant genes.
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PMID:Genetic variance contributes to ingestive processes: a survey of 2-deoxy-D-glucose-induced feeding in eleven inbred mouse strains. 1642

Genetic variation across inbred and outbred mouse strains have been observed for intake of sweet solutions, salts, bitter tastants and a high-fat diet. Our laboratory recently reported marked strain differences in the amounts and/or percentages of kilocalories of sucrose consumed among 11 inbred and one outbred mouse strains exposed to a wide range of nine sucrose concentrations (0.0001-5%) in two-bottle 24-h preference tests. To assess whether differences in fat intake were similarly associated with genetic variation, the present study examined intake of chow, water and an emulsified fat source (Intralipid) across nine different concentrations (0.00001-5%) in the same 11 inbred and 1 outbred mouse strains using two-bottle 24-h preference tests, which controlled for Intralipid concentration presentation effects, Intralipid and water bottle positions, and measurement of kilocalorie intake consumed as Intralipid or chow. Strains displayed differential increases in Intralipid intake relative to corresponding water with significant effects observed at the seven (BALB/cJ: 0.001% threshold sensitivity), four (AKR/J, C57BL/6J, DBA/2J, SWR/J: 0.5% threshold sensitivity), three (CD-1, C57BL/10J, SJL/J: 1% threshold sensitivity) and two (A/J, CBA/J, C3H/HeJ, 129P3/J: 2% threshold sensitivity) highest concentrations. In assessing the percentage of kilocalories consumed as Intralipid, SWR/J mice consumed significantly more at the three highest concentrations to a greater degree than BALB/cJ, C57BL/6J, CD-1, C3H/HeJ, DBA/J and 129P3/J strains which in turn consumed more than A/J, AKR/J, CBA/J, C57BL/10J and SJL/J mice. Relatively strong (h2 = 0.73-0.79) heritability estimates were obtained for weight-adjusted Intralipid intake at those concentrations (0.001-1%) that displayed the largest strain-specific effects in sensitivity to Intralipid. The identification of strains with diverging abilities to regulate kilocalorie intake when presented with high Intralipid concentrations may lead to the successful mapping of genes related to hedonics and obesity.
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PMID:Genetic variance contributes to ingestive processes: a survey of eleven inbred mouse strains for fat (Intralipid) intake. 1702 44

Recently, quantitative trait loci (QTLs) for body weight and obesity have been mapped in an intercross population between the high body weight-selected mouse line DU6i and the inbred line DBA/2. Most QTLs were highly significant, but had small effects only. Under the hypothesis that small-effect QTLs might result from changes in gene activity, our strategy to identify candidate genes for the observed effects was directed towards the identification of differentially expressed genes. Therefore, here we compare the transcription profile of about 11 000 genes in epididymal fat tissues of males of two high body weight-selected (DU6 and DU6i) and two unselected mouse lines (DUKs and DBA/2). For the hybridisation of GeneChips, we used pooled samples of 20 individual mice. By pair-wise comparisons between selected and unselected mouse lines, a set of 77 genes was identified representing genes whose level of expression differed between obese and lean mouse strains. According to the functional classification of genes, 69 differentially expressed genes were involved in regulatory and metabolic pathways, cell division, cell stability, or immune response, and thus might have an effect on body weight and fat accumulation. 14 out of these genes, occur in QTL regions for body weight or abdominal fat weight. Further analyses are necessary to discriminate between genes directly causing QTL effects and indirectly regulated differentially expressed genes.
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PMID:Differentially expressed genes in adipose tissues of high body weight-selected (obese) and unselected (lean) mouse lines. 1749 47

Multiple-trait analyses have been shown to improve the detection of quantitative trait loci (QTLs) with multiple effects. Here we applied a multiple-trait approach on obesity- and growth-related traits that were surveyed in 275 F2 mice generated from an intercross between the high body weight selected line NMRI8 and DBA/2 as lean control. The parental lines differed 2.5-fold in body weight at the age of 6 weeks. Within the F2 population, the correlations between body weight and weights of abdominal fat weight, muscle, liver and kidney at the age of 6 weeks were about 0.8. A least squares multiple-trait QTL analysis was performed on these data to understand more precisely the cause of the genetic correlation between body weight, body composition traits and weights of inner organs. Regions on Chr 1, 2, 7 and 14 for body weights at different early ages and regions on Chr 1, 2, 4, 7, 14, 17 and 19 for organ weights at 6 weeks were found to have significant multiple effects at the genome-wide level.
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PMID:Multiple-trait QTL mapping for body and organ weights in a cross between NMRI8 and DBA/2 mice. 1751 59

An F(2) pedigree based on the mouse lines DU6i and DBA/2 with extremely different growth and obesity characteristics was generated to search for QTLs affecting serum concentrations of triglycerides (TG), total cholesterol (CHOL), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C). Compared with many other studies, we searched for spontaneous genetic variants contributing to high lipid levels under a standard breeding diet. Significant QTLs for CHOL were identified on chromosomes 4 and 6, and a female-specific locus on chromosome 3. QTLs for HDL-C were detected on chromosome 11 for both sexes, and on chromosome 1 for females. These QTLs are located in syntenic human regions that have QTLs that have not been previously confirmed in animal studies. LDL-C QTLs have been mapped for both sexes to chromosome 8 and in males on chromosome 13. Epistatic interactions that significantly accounted for the phenotypic variance of HDL-C, CHOL, and LDL-C serum concentrations were also detected with one interaction between chromosomes 8 and 15, accounting for 22% of the observed variance in LDL-C levels. The identified loci coincide in part with regions controlling growth and obesity. Thus, multiple genes or pleiotropic effects may be assumed. The identified QTLs for cholesterol and its transport proteins as subcomponents of risk for coronary heart disease will further improve our understanding of the genetic net controlling plasma lipid concentrations.
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PMID:Genetic control of lipids in the mouse cross DU6i x DBA/2. 1799 32


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