Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content

Horvat, Simon; Bünger, L.; Falconer, Victoria M.; Mackay, Pamela; Law, Andy; Bulfield, Grahame; Keightley, Peter D.

doi:10.1007/s003350010002

Cited by 77 publications

(74 citation statements)

References 24 publications

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“…Chow-fed male Fat and Lean mice were killed at 8:00 A.M. (the diurnal nadir for corticosterone in mice) for analysis of gene expression and enzyme activities. Fat mice exhibited substantially higher adipose depot-to-body weight ratios than Lean mice (Table 1), as previously described (22)(23)(24). Notably, Fat mice had a proportionately higher subcutaneous and epididymal fat mass relative to the metabolically disadvantageous (1,4) visceral mass, compared with Lean mice (Table 1).…”

Section: Resultssupporting

confidence: 76%

“…One example is proopiomelanocortin (POMC)-null mice (36), where centrally driven, melanocortin-deficient hyperphagia models a rare monogenic obesity syndrome in humans (2). The POMC gene (a precursor for ACTH) maps within the chromosome 12 obesity quantitative trait loci of Fat mice (24) and was therefore an attractive candidate for mediating reduced ACTH, low corticosterone, and obesity (36). However, Fat and Lean mice had similar arcuate nucleus POMC expression levels (V.D., unpublished observations) and relative hypophagia, indicating that central POMC as well as primary leptin (23) and neuropeptide Y (37) defects were not contributory.…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, we tested the hypothesis that altered circulating and peripheral glucocorticoid action underlies obesity and metabolic disease in a "genetically idiopathic" model of murine obesity (22) that has been developed by selection for divergent body fat content for Ͼ47 genera-tions and that is independent of leptin, the leptin receptor system (23), and other single-gene obesity loci (24).…”

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confidence: 99%

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A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action

et al. 2005

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Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1). Indeed, 11␤-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11␤-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11␤-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11␤-HSD-1. Diabetes 54:3371-3378, 2005 I diopathic obesity is highly prevalent and strongly associated with other comorbid conditions such as insulin resistance, type 2 diabetes, dyslipidemia, and hypertension (the metabolic syndrome) (1). Despite major advances in understanding rare monogenic causes of obesity in humans and their striking recapitulation in transgenic or mutant rodent models (2), there is no consensus on a unified underlying biological mechanism accounting for the broader incidence of the metabolic syndrome because of its complex (3) polygenic origins.Close phenotypic parallels exist between idiopathic metabolic syndrome and plasma cortisol excess (e.g., Cushing's syndrome) (4), suggesting a common underlying role for glucocorticoid action in these disease processes. Indeed, rodent obesity and metabolic disease are ameliorated by adrenalectomy (5) and reinstated by exogenous glucocorticoids. Mechanistically, glucocorticoids mediate exaggerated adipocyte formation and hypertrophy (6,7), elevate liver glucose (8) and lipid production (9), exacerbate muscle insulin resistance (10), and inhibit central energy expenditure systems (11). However, in idiopathic human obesity, circulating glucocorticoid levels are usually unaltered, or even low (12). A potential explanation for this paradox is increased amplification of active glucocorticoid levels by the intracellular enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1). 11␤-HSD-1 is elevated in the subcutaneous adipose tissue of obese humans (13-15) and in vis...

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Section: Resultssupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action

et al. 2005

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“…This study focuses on the discovery of QTL accountselected from a common base population (Moody et al ing for phenotypic differences resulting from direct and 1999; Horvat et al 2000). Such crosses are required correlated responses to 27 generations of selection for to differentiate the subset of QTL that have contributed 3-to 6-week weight gain in mice.…”

Section: Or Between Lines Divergentlymentioning

confidence: 99%

Genomic Mapping of Direct and Correlated Responses to Long-Term Selection for Rapid Growth Rate in Mice

2005

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Understanding the genetic architecture of traits such as growth, body composition, and energy balance has become a primary focus for biomedical and agricultural research. The objective of this study was to map QTL in a large F 2 (n ϭ 1181) population resulting from an intercross between the M16 and ICR lines of mice. The M16 line, developed by long-term selection for 3-to 6-week weight gain, is larger, heavier, fatter, hyperphagic, and diabetic relative to its randomly selected control line of ICR origin. The F 2 population was phenotyped for growth and energy intake at weekly intervals from 4 to 8 weeks of age and for body composition and plasma levels of insulin, leptin, TNF␣, IL6, and glucose at 8 weeks and was genotyped for 80 microsatellite markers. Since the F 2 was a cross between a selection line and its unselected control, the QTL identified likely represent genes that contributed to direct and correlated responses to longterm selection for rapid growth rate. Across all traits measured, 95 QTL were identified, likely representing 19 unique regions on 13 chromosomes. Four chromosomes (2, 6, 11, and 17) harbored loci contributing disproportionately to selection response. Several QTL demonstrating differential regulation of regional adipose deposition and age-dependent regulation of growth and energy consumption were identified.

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“…This has been amply demonstrated in recent years with the identification of increasing numbers of quantitative trait loci (QTL) affecting these characters [5,6,11,13,15,26,35,37,43,44]. Most of these QTL studies have been conducted with mice because of the availability of inbred strains or selected lines that are chosen or bred for divergence in the mean of the character of interest and crossed to yield individuals in the F 2 generation with genotypic variability at a number of loci controlling the character [14].…”

Section: Introductionmentioning

confidence: 99%

Genetic variance and covariance patterns for body weight and energy balance characters in an advanced intercross population of mice

et al. 2005

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-We estimated heritabilities and genetic correlations for a suite of 15 characters in five functional groups in an advanced intercross population of over 2000 mice derived from a cross of inbred lines selected for high and low heat loss. Heritabilities averaged 0.56 for three body weights, 0.23 for two energy balance characters, 0.48 for three bone characters, 0.35 for four measures of adiposity, and 0.27 for three organ weights, all of which were generally consistent in magnitude with estimates derived in previous studies. Genetic correlations varied from −0.65 to +0.98, and were higher within these functional groups than between groups. These correlations generally conformed to a priori expectations, being positive in sign for energy expenditure and consumption (+0.24) and negative in sign for energy expenditure and adiposity (−0.17). The genetic correlations of adiposity with body weight at 3, 6, and 12 weeks of age (−0.29, −0.22, −0.26) all were negative in sign but not statistically significant. The independence of body weight and adiposity suggests that this advanced intercross population is ideal for a comprehensive discovery of genes controlling regulation of mammalian adiposity that are distinct from those for body weight.advanced intercross mice / body weight / genetic correlations / heritability / obesity

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Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content

Cited by 77 publications

References 24 publications

A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action

A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action

Genomic Mapping of Direct and Correlated Responses to Long-Term Selection for Rapid Growth Rate in Mice

Genetic variance and covariance patterns for body weight and energy balance characters in an advanced intercross population of mice

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