Journal
CELL
Volume 164, Issue 3, Pages 353-364Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.12.025
Keywords
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Categories
Funding
- Max-Planck Society, ERC [ERC-StG-281641]
- DFG [SFB992, SFB 1052]
- EU_FP7 [279153]
- BMBF (DEEP)
- MRC [MRC_MC_UU_12012/1]
- Wellcome Trust [095515/Z/11/Z]
- German Research Council (DFG) [CRC1052/1 C05]
- Federal Ministry of Education and Research, Germany, FKZ [01EO1001]
- MRC [G0600717, MR/J001597/1, MC_UU_12012/1, G0900554, MC_UU_12012/5, MR/L00027X/1] Funding Source: UKRI
- Medical Research Council [G0900554, MC_PC_12009, MC_UU_12012/5, MR/J001597/1, G0600717B, MC_UU_12012/5/B, MR/L00027X/1, MC_UU_12012/1, G0600717] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10380] Funding Source: researchfish
- Wellcome Trust [095606/Z/11/Z] Funding Source: researchfish
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More than one-half billion people are obese, and despite progress in genetic research, much of the 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 independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
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