Loss of function of Ifi202b by a microdeletion on chromosome 1 of C57BL/6J mice suppresses 11β-hydroxysteroid dehydrogenase type 1 expression and development of obesity.
Nob3 is a major obesity quantitative trait locus (QTL) identified in an intercross of New Zealand Obese (NZO) mice with C57BL/6J (B6), and by introgression of its 38 Mbp peak region into B6 (B6.NZO-Nob3.38). B6.NZO-Nob3.38 mice carrying the NZO allele exhibited markedly increased body weight, fat mass, lean mass and a lower energy expenditure, than the corresponding B6 allele carriers. For positional cloning of the responsible obesity gene, five additional congenic lines (RCS) were generated and characterized, allowing to define a critical genomic interval comprising 43 genes. mRNA profiling and western blotting indicated that Ifi202b, a member of the Ifi200 family of interferon inducible transcriptional modulators, was expressed in NZO-allele carriers but was undetectable in tissues of homozygous B6-allele carriers due to a microdeletion, including the first exon and the 5'-flanking region of Ifi202b in B6. Transcriptome analysis of adipose tissue of RCS revealed a marked induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-Hsd1) expression in mice expressing Ifi202b. Furthermore, siRNA-mediated Ifi202b suppression in 3T3-L1 adipocytes resulted in a significant inhibition of 11β-Hsd1 expression, whereas an adenoviral-mediated overexpression of Ifi202b increased 11β-Hsd1 mRNA levels. Expression of human IFI orthologues was significantly increased in visceral adipose tissue of obese subjects. We suggest that the disruption of Ifi202b in B6 is responsible for the effects of the obesity QTL Nob3, and that Ifi202b modulates fat accumulation through expression of adipogenic genes such as 11β-Hsd1.
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Heike
H
Vogel
Stephan
S
Scherneck
Timo
T
Kanzleiter
Verena
V
Benz
Reinhart
R
Kluge
Mandy
M
Stadion
Sergiy
S
Kryvych
Matthias
M
Blüher
Nora
N
Klöting
Hans-Georg
HG
Joost
Annette
A
Schürmann
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism; D024506:5' Flanking Region / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D009765:Obesity / Q000201:enzymology* / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D055815:Young Adult
C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1