Leptin is an adipokine that regulates food intake and energy expenditure by activating its hypothalamic leptin receptor (LR). Members of the insulin receptor substrate (IRS) family serve as adaptor proteins in the signaling pathways of several cytokines and hormones and a role for IRS2 in central leptin physiology is well established. Using MAPPIT, a cytokine receptor-based two-hybrid method, in the N38 hypothalamic cell line, we here demonstrate that also IRS4 interacts with the leptin receptor. This recruitment is leptin-dependent and requires phosphorylation of the Y1077 motif of the LR. Domain mapping of IRS4 revealed the critical role of the Pleckstrin Homology (PH) domain for full interaction. In line with its function as an adaptor protein, IRS4 interacted with the regulatory p85 subunit of the PI3K, PLC and the SOCS family members SOCS2, SOCS6, and SOCS7, and thus can modulate LR signaling.