A proximal genomic region of mouse chromosome 10 contains quantitative trait loci affecting fatness

Ishikawa, Akira; Tanahashi, Takahisa; Kodama, Hiroyuki

doi:10.1111/j.1740-0929.2010.00842.x

Cited by 2 publications

(2 citation statements)

References 26 publications

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“…In this study, we used wild M. m. castaneus mice captured in the Philippines that have only 60% of the body weight of the B6 strain [ 17 ]. The obesity-resistant QTL allele derived from the wild castaneus mouse must reflect variation in nature, because males obtained from a cross of wild-caught mice were directly used to map QTLs for body weight and growth [ 17 ] and thereafter some of the wild-derived QTL alleles discovered have been saved by development of congenic strains [ 6 , 27 , 28 ]. Other studies using wild mice, including M. m. molossinus and M. m. castaneus , have revealed several loci related to growth, obesity, aging, abnormal spermatogenesis, and diabetes [ 29 - 33 ].…”

Section: Discussionmentioning

confidence: 99%

A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity

Mollah

Ishikawa

2010

BMC Genet

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BackgroundThe genetic architecture of multifactorial traits such as obesity has been poorly understood. Quantitative trait locus (QTL) analysis is widely used to localize loci affecting multifactorial traits on chromosomal regions. However, large confidence intervals and small phenotypic effects of identified QTLs and closely linked loci are impeding the identification of causative genes that underlie the QTLs. Here we developed five subcongenic mouse strains with overlapping and non-overlapping wild-derived genomic regions from an F2 intercross of a previously developed congenic strain, B6.Cg-Pbwg1, and its genetic background strain, C57BL/6J (B6). The subcongenic strains developed were phenotyped on low-fat standard chow and a high-fat diet to fine-map a previously identified obesity QTL. Microarray analysis was performed with Affymetrix GeneChips to search for candidate genes of the QTL.ResultsThe obesity QTL was physically mapped to an 8.8-Mb region of mouse chromosome 2. The wild-derived allele significantly decreased white fat pad weight, body weight and serum levels of glucose and triglyceride. It was also resistant to the high-fat diet. Among 29 genes residing within the 8.8-Mb region, Gpd2, Upp2, Acvr1c, March7 and Rbms1 showed great differential expression in livers and/or gonadal fat pads between B6.Cg-Pbwg1 and B6 mice.ConclusionsThe wild-derived QTL allele prevented obesity in both mice fed a low-fat standard diet and mice fed a high-fat diet. This finding will pave the way for identification of causative genes for obesity. A further understanding of this unique QTL effect at genetic and molecular levels may lead to the discovery of new biological and pathologic pathways associated with obesity.

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Section: Discussionmentioning

confidence: 99%

A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity

Mollah

Ishikawa

2010

BMC Genet

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“…Body mass index (BMI) was used to evaluate adiposity [26] and calculated according to the formula BMI = mass (g)/(length [cm]) 2 . WAT was dissected from the intra-abdominal region, BAT from the interscapular region, and fat pads from the subcutaneous areas that overlie the proximal femurs.…”

Section: Methodsmentioning

confidence: 99%

Paternally Inherited Gsα Mutation Impairs Adipogenesis and Potentiates a Lean Phenotype In Vivo

et al. 2012

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Paternally inherited inactivating mutations of the GNAS gene have been associated with a rare and disabling genetic disorder, progressive osseous heteroplasia, in which heterotopic ossification occurs within extraskeletal soft tissues, such as skin, subcutaneous fat, and skeletal muscle. This ectopic bone formation is hypothesized to be caused by dysregulated mesenchymal progenitor cell differentiation that affects a bipotential osteogenic-adipogenic lineage cell fate switch. Interestingly, patients with paternally inherited inactivating mutations of GNAS are uniformly lean. Using a mouse model of Gsα-specific exon 1 disruption, we examined whether heterozygous inactivation of Gnas affects adipogenic differentiation of mesenchymal precursor cells from subcutaneous adipose tissues (fat pad). We found that paternally inherited Gsα inactivation (Gsα+/p−) impairs adipogenic differentiation of adipose-derived stromal cells (ASCs). The Gsα+/p− mutation in ASCs also decreased expression of the adipogenic factors CCAAT-enhancer-binding protein (C/EBP)β, C/EBPα, peroxisome proliferator-activated receptor gamma, and adipocyte protein 2. Impaired adipocyte differentiation was rescued by an adenylyl cyclase activator, forskolin, and provided evidence that Gsα-cAMP signals are necessary in early stages of this process. Supporting a role for Gnas in adipogenesis in vivo, fat tissue weight and expression of adipogenic genes from multiple types of adipose tissues from Gsα+/p− mice were significantly decreased. Interestingly, the inhibition of adipogenesis by paternally inherited Gsα mutation also enhances expression of the osteogenic factors, msh homeobox 2, runt-related transcription factor 2, and osteocalcin. These data support the hypothesis that Gsα plays a critical role in regulating the balance between fat and bone determination in soft tissues, a finding that has important implications for a wide variety of disorders of osteogenesis and adipogenesis.

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A proximal genomic region of mouse chromosome 10 contains quantitative trait loci affecting fatness

Cited by 2 publications

References 26 publications

A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity

A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity

Paternally Inherited Gsα Mutation Impairs Adipogenesis and Potentiates a Lean Phenotype In Vivo

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