The Molecular Genetics
of Body Weight Regulation
RUDOLPH L. LEIBEL
That genes exist for body weight and composition in animals is apparent from the autosomal recessive and dominant obesity mutations in rodents, transgenic experiments in mice, single gene mutations affecting muscle mass in cattle and sheep, and strainrelated differences in body composition in domesticated cattle, pigs, sheep, and other animals. The concordance of somatic phenotype among mono- and dizygous twins, and adopted children and their respective parents, as well as segregation analyses of relative adiposity in families, indicate a substantial genetic contribution to body fatness (see Chapters 3 and 4). Single gene/locus mutations that produce obesity in humans are also well documented (see below).
The genes determining fatness must affect energy intake, energy expenditure, or partitioning (the molecular form; e.g., fat, glycogen, and proteins in which calories are stored in the body). Such genes can affect all three of these major phenotypes or may affect only one or two of them. Body mass and composition reflect the lifetime effects of these three phenotypes, so small imbalances persisting over time can have large effects. Therefore, despite potent genetic influences on body fat, it is difficult to implicate specific genes in any but the rare instances of obesity that are inherited in Mendelian fashion.
Most observed Mendelian variation in phenotype is due to DNA sequence variation in a single gene. For non-Mendelian, complex or polygenic traits, phenotype variation reflects allelic variation in several or many genes and their interactions with each other and the environment. The recent applications of linkage analysis and positional cloning to Mendelian phenotypes have succeeded where the correlations between single-locus genotype and phenotype are strong, and where the effect of genotype is large.