Presentation by Claude Bouchard, M.D., Universite Laval, Quebec, Canada, at AAAS symposium on "Gene-Diet Interactions in Coronary Heart Disease"
There are considerable individual differences in the response to chronic overfeeding for body mass, body composition and a variety of metabolic phenotypes.
We have used an experimental model based on identical twins subjected to treatments lasting for weeks or months to try to identify whether the genes were involved in the heterogeneity in responsiveness. Two overfeeding experiments were undertaken with a total of 18 pairs of young adult male identical twins, and two negative energy balance intervention protocols were executed with the participation of 13 pairs of identical twins.
The results of the most extensive of these experimental protocols are summarized here. Twelve pairs of young adult male monozygotic twins were overfed by 1000 kcal per day, 6 days a week, for a 100-day period. The total excess amount each man consumed was 84,000 kcal. The similarity within each pair in the response to overfeeding was significant with respect to body weight, percent body fat, and subcutaneous fat, with about three times more variance among pairs than within pairs.
After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat with about six times as much variance among pairs as within pairs. The within-pair resemblance for the changes in fasting insulin, insulin response to a glucose load, plasma lipids and lipoproteins was also quite significant but it was reduced when the gains in total body fat were taken into account.
The twins were remeasured 4 months after the overfeeding protocol and again 5 years later. The within-pair resemblance in the post overfeeding changes in body composition, fat distribution, insulin and plasma lipoprotein levels was also quite apparent. These results strongly suggest that undefined genetic factors are associated with individual differences in the response to long term overfeeding. These observations and others from the genetic epidemiology literature strongly suggest that the genes are involved in determining the susceptibility to several manifestations of the metabolic syndrome including cardiovascular disease.
Of considerable interest is the role of the genes in the predisposition to become obese. Among the lines of evidence for a role of the genes, one must include the human linkage studies. Two genomic scans have been reported to date, one from the Pima Indian sibling study and the second from the San Antonio Family Heart Study. In the former, the strongest evidence for linkage with body fat was with markers on chromosome 11q21-q22, 6p21.3 and 3p24.2-p22, while in the latter it was with markers on 2p21. Evidence for linkage with markers on 7q33 was obtained in all family studies with the only apparent exception being the Pima Indians.
Our own results from the Quebec family Study suggests that there are linkages between body fat, as assessed from hydrodensitometry, and markers on 1p32-p22. In addition, significant linkages have also been obtained in QFS for markers spanning the region from the ADA locus to the MC3R locus on 20q12-q13 and with MC5R on 18p11.2. Other linkages have been reported in the past but they are generally based on weaker evidence.
All these results will be summarized and discussed with respect to candidate genes and genome wide scan initiatives. The stage is now set for major advances to occur in the understanding of the genetic and molecular basis of the responsiveness to various dietary regimens and of complex diseases such as human obesity.
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