Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model.

West, David B.; Goudey-Lefevre, Jo; York, Barbara; Truett, Gary E.

doi:10.1172/jci117477

Cited by 140 publications

(64 citation statements)

References 33 publications

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“…Comparative genome analysis data showed that Ins/gk1 and Chol/gk1 are conserved with a region of mouse chromosome 9, previously characterised for the obesity QTL Dob2 and Mob8 [23,24,25], and human chromosomes 11q22.3-24.3, 15q21.2-25.1 and 6p21.1-q14.1. The region of human 15q, which contains the locus LIPC and is associated with variations in HDL-C concentrations in Mexican Americans [26], seems to be homologous to Chol/gk1.…”

Section: Discussionmentioning

confidence: 87%

Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

et al. 2004

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Aims/hypothesis. Genetic investigations in the spontaneously diabetic (Type 2) Goto Kakizaki (GK) rat have identified quantitative trait loci (QTL) for diabetes-related phenotypes. The aims of this study were to refine the chromosomal mapping of a QTL (Nidd/gk5) identified in chromosome 8 of the GK rat and to define a pathophysiological profile of GK gene variants underlying the QTL effects in congenics. Methods. Genetic linkage analysis was carried out with chromosome 8 markers genotyped in a GKxBN F2 intercross previously used to map diabetes QTL. Two congenic strains were designed to contain GK haplotypes in the region of Nidd/gk5 transferred onto a Brown Norway (BN) genetic background, and a broad spectrum of diabetes phenotypes were characterised in the animals. Results. Results from QTL mapping suggest that variations in glucose-stimulated insulin secretion in vivo, and in body weight are controlled by different chromosome 8 loci (LOD3.53; p=0.0004 and LOD4.19; p=0.00007, respectively). Extensive physiological screening in male and female congenics at 12 and 24 weeks revealed the existence of GK variants at the locus Nidd/gk5, independently responsible for significantly enhanced insulin secretion and increased levels of plasma triglycerides, phospholipids and HDL, LDL and total cholesterol. Sequence polymorphisms detected between the BN and GK strains in genes encoding ApoAI, AIV, CIII and Lipc do not account for these effects. Conclusions/interpretation. We refined the localisation of the QTL Nidd/gk5 and its pathophysiological characteristics in congenic strains derived for the locus. These congenic strains provide novel models for testing the contribution of a subset of GK alleles on diabetes phenotypes and for identifying diabetes susceptibility genes.

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Section: Discussionmentioning

confidence: 87%

Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

et al. 2004

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“…4 In fact, for at least 13 QTL, evidence for linkage of body weight and body fat percentage was found within the same study, including Adip2, Adip3, Adip4a, Adip8, Bfq1, Bwnd5wk6, Do2, Do3, Do7, Kcal3, Nob1, Nzoq2, and Obq5. [51][52][53][54][55][56][57][58][59][60] It appears that most of these QTL involved cross-breeding experiments with parental mouse strains that show a relatively high (AKR, NZO, KK) and low (CAST, SM, SJL) body weight and (Figures 2 and 3). The contribution of QTL to certain consensus regions apparently correlates with the parental mouse strain.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice

et al. 2006

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Objective: Cross-breeding experiments with different mouse strains have successfully been used by many groups to identify genetic loci that predispose for obesity. In order to provide a statistical assessment of these quantitative trait loci (QTL) as a basis for a systematic investigation of candidate genes, we have performed a meta-analysis of genome-wide linkage scans for body weight and body fat. Data: From a total of 34 published mouse cross-breeding experiments, we compiled a list of 162 non-redundant QTL for body weight and 117 QTL for fat weight and body fat percentage. Collectively, these studies include data from 42 different parental mouse strains and 414 500 individual mice. Methods: The results of the studies were analyzed using the truncated product method (TPM). Results: The analysis revealed significant evidence (logarithm of odds (LOD) score 44.3) for linkage of body weight and adiposity to 49 different segments of the mouse genome. The most prominent regions with linkage for body weight and body fat (LOD scores 14.8-21.8) on chromosomes 1, 2, 7, 11, 15, and 17 contain a total of 58 QTL for body weight and body fat. At least 34 candidate genes and genetic loci, which have been implicated in regulation of body weight and body composition in rodents and/or humans, are found in these regions, including CCAAT/enhancer-binding protein alpha (C/EBPA), sterol regulatory element-binding transcription factor 1 (SREBP-1), peroxisome proliferator activator receptor delta (PPARD), and hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1). Our results demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control body weight and body composition. An interactive physical map of the QTL is available online at

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“…This finding is not unprecedented. In studies of genetic modifiers of the L e p r f a mutation, Chung et al (29) found that the susceptibility alleles to L e p r f a -associated diabetes are not always derived from the susceptible strain, a phenomenon known as "transgression" that has also been seen in studies of QTL controlling body fat and diet (46,47). A possible explanation is that these alleles are silenced by more dominant alleles in the context of the resistant strain but are active in the context of the susceptible strain.…”

Section: Ta B L E 2 Distribution Analysis (mentioning

confidence: 99%

Genetic modifiers of the insulin resistance phenotype in mice.

et al. 2000

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Insulin resistance can result from genetic interactions among susceptibility alleles. To identify genetic loci predisposing to insulin resistance, we used crosses between different strains of mice with a targeted null allele of the insulin receptor gene. On the genetic background of B6 mice, the insulin receptor gene mutation causes mild hyperinsulinemia. In contrast, on the genetic background of 129/Sv mice, the same mutation causes severe hyperinsulinemia, suggesting that the 129/Sv strain harbors alleles that interact with the insulin receptor mutation and predispose to insulin resistance. As a first step to identify these alleles, we generated an F 2 intercross between insulin receptor heterozygous mutant mice on B6 and 129/Sv backgrounds (B6 I R 1 2 9 I R ) and performed a genome-wide scan with polymorphic markers at a 20-cM resolution. We report the identification of loci on chromosomes 2 (logarithm of odds [LOD] 5.58) and 10 (LOD 5.58) that show significant evidence for linkage to plasma insulin levels as a quantitative trait. These findings indicate that targeted mutations in knockout mice can be used to unravel the complex genetic interactions underlying insulin resistance. Diabetes 4 9 :5 8 9-596, 2000

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Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model.

Cited by 140 publications

References 33 publications

Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice

Genetic modifiers of the insulin resistance phenotype in mice.

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