Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity

The insulin-like growth factor 2 gene (Igf2) is imprinted in most somatic t issues of the mouse with the exception of the choroid plexus and leptomenin ges of the brain, where it is expressed from both alleles, The imprinting o f lgf2 is dependent upon an imprinting control region (ICR) that lies 90 kb 3 ' of the gene and acts as a chromatin insulator to block enhancers that lie further 3 ' on the chromosome. Based on this model we would expect that enhancers of brain-specific expression of lgf2 would lie 5 ' of the ICR, a nd thus be insensitive to its action, Here we describe a 12 kb deletion of a region 5 ' of the ICR that is hypersensitive to nuclease digestion in chr omatin, Its deletion results in a biallelic decrease in expression of lgf2, but not H19, in the brain, consistent with the proposal that it encodes a positive regulatory element. In addition, the deletion results in a minor r elaxation of lgf2 imprinting in skeletal muscle and tongue. Lastly, the red uction in IGFII expression in the adult is accompanied by increased fat dep osition and occasional obesity, Overweight animals are hypophagic, suggesti ng that IGFII affects fat metabolism rather than feeding behavior in adult mice.