Maternal environment and genotype interact to establish diabesity in mice.

Obesity, a major risk factor for type II diabetes, is becoming more prevalent in Western populations consuming high calorie diets while expending less energy both at the workplace and at home. Most human obesity, and probably most type II diabetes as well, reflects polygenic rather than monogenic inheritance. We have genetically dissected a polygenic mouse model of obesity-driven type II diabetes by outcrossing the obese, diabetes-prone, NZO (New Zealand Obese)/HlLt strain to the relatively lean NON (Nonobese Nondiabetic)/Lt strain, and then reciprocally backcrossing obese F1 mice to the lean NON/Lt parental strain. A continuous distribution of body weights was observed in a population of 203 first backcross males. The 22% of first backcross males developing overt diabetes showed highest peripubertal weight gains and earliest development of hyperinsulinemia. We report a complex diabetes-predisposing ("diabesity") QTL (Quantitative Trait Loci) on chromosome 1 contributing significant main effects to increases in body weight, plasma insulin, and plasma glucose. NZO contributed QTL with significant main effects on adiposity parameters on chromosomes 12 and 5. A NON QTL on chromosome 14 interacted epistatically with the NZO obesity QTL on chromosome 12 to increase adiposity. Although the main effect of the diabetogenic QTL on chromosome 1 was on rapid growth rather than adiposity, it interacted epistatically with the obesity QTL on chromosome 12 to increase plasma glucose levels. Additional complex epistatic interactions eliciting significant increases in body weight and/or plasma glucose were found between the NZO-contributed QTL on chromosome 1 and other NZO-contributed QTL on chromosomes 15 and 17, as well as with an NON-contributed QTL on chromosome 2. We further show that certain of these intergenic interactions are predicated on, or enhanced by, the maternal postparturitional environment. We show by cross-fostering experiments that the maternal environmental influence in part is because of the presence of early obesity-inducing factors in the milk of obese F1 dams. We also discuss a strategy for using recombinant congenic strains to separate and reassemble interacting QTL for future study.

[1]  G. Yule.  NOTES ON THE THEORY OF ASSOCIATION OF ATTRIBUTES IN STATISTICS , 1903 .

[2]  Nancy J. Cox,et al.  Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans , 1999, Nature Genetics.

[3]  D. Beier,et al.  Genetic localization of interacting modifiers affecting severity in a murine model of polycystic kidney disease. , 2000, Genome research.

[4]  B. Koletzko,et al.  Nutritional and biochemical properties of human milk, Part I: General aspects, proteins, and carbohydrates. , 1999, Clinics in perinatology.

[5]  B. Levin,et al.  Gestational obesity accentuates obesity in obesity-prone progeny. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[6]  M. Pietropaolo,et al.  Controversial topics series: Milk proteins and diabetes , 1999, Journal of endocrinological investigation.

[7]  P. Björntorp.  Androgens, the Metabolic Syndrome, and Non–Insulin‐Dependent Diabetes Mellitus , 1993, Annals of the New York Academy of Sciences.

[8]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[9]  B. Taylor,et al.  Detection of obesity QTLs on mouse chromosomes 1 and 7 by selective DNA pooling. , 1996, Genomics.

[10]  J. Friedman,et al.  Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. O’Connell,et al.  Evidence for a Major Gene for Type II Diabetes and Linkage Analyses With Selected Candidate Genes in Mexican-Americans , 1996, Diabetes.

[12]  H. Kuwano,et al.  Genetic analysis of obese diabetes in the TSOD mouse. , 1999, Diabetes.

[13]  A. Clark,et al.  Limits to Prediction of Phenotypes from Knowledge of Genotypes , 2000 .

[14]  A. Attie,et al.  Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[15]  E. Leiter,et al.  Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin. , 1998, Journal of immunology.

[16]  T. Ogihara,et al.  Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait. , 1999, Diabetes.

[17]  E. H. Simpson,et al.  The Interpretation of Interaction in Contingency Tables , 1951 .

[18]  J. Naggert,et al.  Gene-environment interaction: a significant diet-dependent obesity locus demonstrated in a congenic segment on mouse Chromosome 7 , 1999, Mammalian Genome.

[19]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[20]  Berthold Koletzko,et al.  Breast feeding and obesity: cross sectional study , 1999, BMJ.

[21]  E. Leiter,et al.  NIDDM Genes in Mice: Deleterious Synergism by Both Parental Genomes Contributes to Diabetogenic Thresholds , 1998, Diabetes.

[22]  M. McCarthy,et al.  Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families , 1996, Nature Genetics.

[23]  Kenneth F. Manly,et al.  Overview of QTL mapping software and introduction to Map Manager QT , 1999, Mammalian Genome.

[24]  R. S. Spielman,et al.  A genome–wide search for human non–insulin–dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2 , 1996, Nature Genetics.

[25]  Y. Kido,et al.  Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. , 2000, The Journal of clinical investigation.

[26]  R. Pratley.  Gene–environment interactions in the pathogenesis of type 2 diabetes mellitus: lessons learned from the Pima Indians , 1998, Proceedings of the Nutrition Society.

[27]  W. Frankel,et al.  A major effect QTL determined by multiple genes in epileptic EL mice. , 2000, Genome research.