The Molecular Genetics of Rodent Single Gene Obesities

Only three fundamental mechanisms can underlie the development of obesity: 1) relative increase in energy intake; 2) relative decrease in energy expenditure; and 3) preferential partitioning of ingested calories to fat storage. That any one of these defects is sufficient to cause obesity is demonstrated by the phenotypes of animals produced by specific transgenic manipulations as follows. 1) Disruption of the 5HT2c serotonin receptor results in hyperphagia and obesity (1). 2) Defective nonshivering thermogenesis (energy expenditure) is the major abnormality in obese mice with ablation of brown adipose tissue due to tissue-specific expression of the diphtheria toxin gene driven by the uncoupling protein promoter (2).