Characterization of a novel obesity phenotype caused by interspecific hybridization.
Interspecific hybridization in mammals causes hybrid dysgenesis effects, such as sterility and abnormal placentation. Here, we describe a novel obesity syndrome caused by interspecific hybridization in the genus Mus and show that this obesity, appearing sporadically in F1 littermates derived from inbred strains, has an epigenetic basis. Mus hybrids from various strains of M. musculus and M. spretus were generated and the sporadic obese phenotype was confirmed through assessment of physiological and biochemical parameters in littermates. To understand the underlying mechanisms, large-scale and candidate gene expression assays, global DNA methylation assays and allelic expression analysis were performed. Studies showed that obese hybrids are similar to other known models of obesity. While increased axial growth indicated a defect in POMC pathway, comparison of global gene expression patterns in brain of obese F1 and obese Pomc mutant mice showed little similarity. In F1 obese mice many genes involved in the maintenance of epigenetic states, as well as several imprinted genes, were differentially expressed. Global DNA methylation analysis in brain showed that increased methylation levels were associated with obesity. The imprinted gene Gnasxl, known to be important in lipid homeostasis, was found over expressed in the obese hybrids. Allelic expression and methylation analysis of Gnasxl showed that alterations of epigenetic marks underlying F1 obesity are probably many and multi-factorial.


CONCLUSIONS
This model of obesity, which is both spontaneous and epigenetic, may be a useful tool to address the epigenetic aspects of clinical obesity.
Singh
Umashankar
U
Department of Development and Genetics, Evolutionary Biology Center, Uppsala University, Uppsala, Sweden.
Rizvi
Farhan
F
Yu
Yang
Y
Shi
Wei
W
Orth
Annie
A
Karimi
Mohsen
M
Ekström
Tomas J
TJ
Plagge
Antonius
A
Kelsey
Gavin
G
Fundele
Reinald
R
D000818:Animals; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000235:genetics; D006824:Hybridization, Genetic / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype