Dysregulation of an imprinted gene network reproducibly produces lean and obese, but not intermediate, phenotypes in both mouse and man, according to a new study by J. Andrew Pospisilik and colleagues. This phenomenon, termed bi-stable epigenetic obesity by the investigators, suggests that polyphenism — distinct phenotypes produced by the same genotype — exists in mammals.

Analysis of large cohorts of isogenic Trim28 haploinsufficient mice (controlled for factors influencing growth and metabolism) revealed two discrete populations of offspring: one obese (with increased adipose depot mass) and the other lean. Obesity was inherited in a non-Mendelian manner and the two phenotypes persisted 7 years of backcrossing and inbreeding. Characterization of the molecular events underlying the obese state in Trim28 mutant mice revealed downregulation of the IGN1 imprinted gene network, which includes Nnat1, Peg3, Cdkn1c and Plag1. Targeted deletion of select members of this gene cluster recapitulated the phenotypes of Trim28 haploinsufficient mice, with offspring being either lean or obese. These findings confirm that IGN1 dysregulation specifies 'on' and 'off' obese states.

To investigate whether bi-stable epigenetic obesity also exists in humans, the researchers performed transcriptome analysis of adipose tissue samples from lean and obese pre-pubertal children. Compared with lean children, those with obesity had marked reductions in both TRIM28 levels in adipose tissue and IGN1 pathway expression, mimicking the results from Trim28 haploinsufficient mice. Furthermore, analysis of BMI distributions in the general population suggested the existence of two different subpopulations, consistent with the idea of polyphenism.

The findings could explain the 'missing' heritability in genome-wide association studies of obesity. “These studies assume that major digital (on/off) and stable epigenetic phenotypes like the one here, do not exist,” explains Pospisilik. “We show that they do.”