Identification and characterization of an insulin receptor substrate 4-interacting protein in rat brain: implications for longevity.

The hypothalamus is organized as a collection of distinct, autonomously active nuclei that regulate discrete functions, such as feeding activity and metabolism. We used suppression subtractive hybridization (SSH) to identify genes that are enriched in the hypothalamus of the rat brain. We screened a subtractive library of 160 clones, and 4 genes that were predominantly expressed in the hypothalamus, compared to other brain regions. The mRNA for a member of the WD-repeat family of proteins, WDR6, was abundantly expressed in the hypothalamus, and we found that WDR6 interacted with insulin receptor substrate 4 (IRS-4) in the rat brain. Interestingly, WDR6 gene expression in the hypothalamic arcuate nucleus was decreased by caloric restriction, and in growth hormone (GH)-antisense transgenic rats, both of which are associated with an increased life span. Insulin-like growth factor (IGF)-I and insulin treatment increased WDR6 gene expression in mouse hypothalamus-derived GT1-7 cells. Our results might suggest that WDR6 participates in insulin/IGF-I signaling and the regulation of feeding behavior and longevity in the brain.