Genetic and environmental approaches to obesity research in the 21st century: A synthesis of 20th century paradigms

In contrast to many other medical conditions, obesity has increased drastically in prevalence throughout the 20th Century. The lack of success in the control of obesity may be traced to the nature of obesity itself because overeating, the immediate cause of obesity, may be the result of any combination of physical, emotional, or social factors. Scientific and medical approaches to understanding and treating obesity reflect this confusion, with alternating paradigms based on both internal and external causality. A history of the development of scientific and medical ideas related to obesity throughout the 20th Century leads to the argument that future directions in obesity research must address the dual causality of obesity as interactively internal and external. As an example, we demonstrated that the SM/J inbred mouse strain responds more strongly to dietary fat than the LG/J inbred mouse strain across a range of obesity and diabetes-related phenotypes, including growth rates, organ weights, fat pad weights, serum lipids, and response to glucose challenge. We followed this by generating an F16 advanced intercross line (AIL) from these parental strains and splitting each family by diet, with half receiving a low fat diet and the other half receiving a high fat diet. A quantitative genetic analysis of this population demonstrated moderate heritability for most traits examined, with high phenotypic and genetic correlations in a number of phenotypes including liver weight, serum insulin, and reproductive fat pad weight. There is little genetic correlation of these phenotypes between the two diets, indicating that gene effects depend on the amount of fat in the diet. Gene by diet interactions were moderately heritable and highly correlated in this trait set, indicating that the genetic basis of dietary response was common for this group of traits. A scan of previously detected adiposity quantitative trait loci (QTL) in the F16 experimental population revealed gene by diet interactions for a number of phenotypes on proximal chromosome 13. Using the Ensembl database, two genes were located in the region of greatest interaction effect. One of these, a phosphofructokinase, differs by 5 amino acids between the SM/J and LG/J parental strains.