Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

More than one-half billion people are obese, and despite progress in genetic research, much of the high heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28 +/D9 mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that indepen- dent targeting of these alleles recapitulates the sto- chastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, tran- scriptome organization, and obesity-associated im- printed gene dysregulation. These data provide evi- dence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.