The insulin receptor substrate (IRS) proteins are a family of important regulatory adapters that mediate the coupling between receptor-associated tyrosine kinases and downstream effectors including phosphatidylinositol-3'-kinases (PI-3-Ks). In the present study, the distribution of IRS-4 mRNA was determined in rat brain by in situ hybridization. IRS-4 mRNA was widely expressed throughout the hypothalamus, with the most dense labeling observed in the medial preoptic nucleus, ventromedial hypothalamus, and arcuate nucleus. In contrast, and unlike IRS-1 or IRS-2, expression of IRS-4 mRNA in other forebrain and midbrain regions was much more restricted. The expression of IRS-4 mRNA in the hypothalamus suggests a specific role for this factor in the signaling of one or more receptors involved hypothalamic functions including feeding, lactation, sexual and parental behaviors.