Schwann cells (SCs) are the principal glia of the peripheral nervous system and are in close contact with axons to ensure a fast propagation of electrical impulses. After nerve injury, myelinating SCs distal to the injury site dedifferentiate into pro-regenerative repair SCs. In a later phase after injury, repair SCs must redifferentiate into myelinating cells to provide a fully functional regenerated nerve. Meyer zu Reckendorf et al. recently showed the important role of metabolic adaptation in SC reprogramming after injury in an ex vivo nerve lesion model. In particular, lipid metabolism downregulation was identified as an essential process for proper SC dedifferentiation after injury. Here, we investigated the role of the transcription factor PPARɣ as a key regulator of lipid metabolism in peripheral nerve regeneration in mice by molecular and functional analyses. In a sciatic nerve crush injury model, lipid metabolism was modulated pharmacologically by the PPARɣ agonist Pioglitazone (PIO) within the early SC degeneration or the later regeneration phase. Early PIO administration disturbed repair SC induction and axonal clearance, affected remyelination, and impaired sensory and motor functional recovery upon sciatic nerve injury. In contrast, late PIO treatment enhanced axonal regrowth and remyelination and improved sensory and motor functional recovery. Thus, time-dependent PPARɣ adaptation seems to play an important role in peripheral nerve regeneration in mice and could be used as a new pharmacological target for improving nerve regeneration.