Characterization of Nob3, a major quantitative trait locus for obesity and hyperglycemia on mouse chromosome 1.
New Zealand obese (NZO) mice present a metabolic syndrome of obesity, insulin resistance, and diabetes. To identify chromosomal segments associated with these traits, we intercrossed NZO mice with the lean and diabetes-resistant C57BL/6J (B6) strain. Obesity and hyperglycemia in the (NZO x B6)F2 intercross population were predominantly due to a broad quantitative trait locus (QTL) on chromosome 1 (Nob3; logarithm of the odds score 16.1, 16.0, 4.0 for body weight, body fat, and blood glucose, respectively), producing a difference between genotypes of 12.7 or 5.2 g of body weight and 12.0 or 4.0 g of body fat in females or males, respectively. In addition, significant QTL on chromosomes 3 and 13 and suggestive QTL on chromosomes 4, 6, 9, 12, 14, and 19 contributed to the obese phenotype. Distal chromosome 5 was significantly linked with plasma cholesterol (LOD score 10.7). Introgression of two segments of Nob3 into B6 confirmed the adipogenic effect of the QTL and suggested the presence of at least one causal gene. Haplotype mapping reduced the critical region of the distal part of the QTL to 31 Mbp containing the potential candidates Nr1i3, Apoa2, Atp1a2, Prox1, and Hsd11b1. We conclude that obesity and hyperglycemia of NZO is to a large part caused by variant genes located in Nob3 on chromosome 1. Since these exert robust effects on a B6 background, the QTL Nob3 is a prime target for identification of a novel diabesity gene.
Vogel
Heike
H
Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Nestler
Matthias
M
Rüschendorf
Franz
F
Block
Marcel-Dominique
MD
Tischer
Sina
S
Kluge
Reinhart
R
Schürmann
Annette
A
Joost
Hans-Georg
HG
Scherneck
Stephan
S
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000235:genetics*; D001823:Body Composition / Q000235:genetics*; D001835:Body Weight / Q000235:genetics*; D002874:Chromosome Mapping; D000090702:Constitutive Androstane Receptor; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D008126:Lod Score; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
D001786:Blood Glucose; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse