Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model

We analyzed the inheritance of body fat, leptin levels, plasma lipoprotein levels, insulin levels, and related traits in an intercross between inbred mouse strains CAST/Ei and C57BL/6J. CAST/Ei mice are unusually lean, with only approximately 8% of body weight as fat, whereas C57BL/6J mice have appr...

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Bibliographic Details
Published in:The Journal of clinical investigation 1998-06, Vol.101 (11), p.2485-2496
Main Authors: Mehrabian, M, Wen, P Z, Fisler, J, Davis, R C, Lusis, A J
Format: Article
Language:English
Subjects:
Adipose Tissue - metabolism
Animals
Carrier Proteins - analysis
Chromosome Mapping
Diabetes Mellitus, Type 2 - etiology
Female
Insulin - blood
Insulin Resistance
Leptin
Lipoproteins - metabolism
Male
Mice
Mice, Inbred Strains
Obesity - genetics
Proteins - analysis
Quantitative Trait, Heritable
Receptors, Cell Surface
Receptors, Leptin
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Summary:We analyzed the inheritance of body fat, leptin levels, plasma lipoprotein levels, insulin levels, and related traits in an intercross between inbred mouse strains CAST/Ei and C57BL/6J. CAST/Ei mice are unusually lean, with only approximately 8% of body weight as fat, whereas C57BL/6J mice have approximately 18% body fat. Quantitative trait locus analysis using > 200 F2 mice revealed highly significant loci (lod scores > 4.3) on chromosomes 2 (three separate loci) and 9 that contribute to mouse fat-pad mass for mice on a high-fat diet. Some loci also influenced plasma lipoprotein levels and insulin levels either on chow or high-fat diets. Two loci for body fat and lipoprotein levels (on central and distal chromosome 2) coincided with a locus having strong effects on hepatic lipase activity, an activity associated with visceral obesity and lipoprotein levels in humans. A locus contributing to plasma leptin levels (lod score 5.3) but not obesity was identified on chromosome 4, near the leptin receptor gene. These data identify candidate regions and candidate genes for studies of human obesity and diabetes, and suggest obesity is highly complex in terms of the number of genetic factors involved. Finally, they support the existence of specific genetic interactions between body fat, insulin metabolism, and lipoprotein metabolism.
ISSN:0021-9738
DOI:10.1172/jci1748