The transcriptional basis of sebocyte differentiation and lipid production is mostly unclear. Peroxisome proliferator-activated receptor gamma (PPARγ), a lipid activated transcription factor, has been implicated in differentiation and lipid metabolism of various cell types. Here, we show that PPARγ is differentially expressed in normal and pathological human sebocytes, and appears to have roles in their differentiation and lipid production. We used laser microdissected normal and pathologic human sebaceous glands (SG) and SZ95 cells (immortalized sebocyte cell line) analyzed by RT-qPCR and immunohistochemistry. Lipids were analyzed by quantitative fluorimetry and mass spectrometry based approaches. We have observed that PPARγ and its target genes, ADRP and PGAR, are expressed in sebocytes and show association with their level of differentiation. Also, PPARγ is present in normal and hyperplastic SG, whereas its expression levels are decreased in SG adenoma and SG carcinoma cells, reflecting a maturation-linked expression pattern. Furthermore, in SZ95 sebocytes, naturally occurring lipids including arachidonic acid and arachidonic acid keto-metabolites (eg 5-KETE, 12-KETE) appear to regulate PPARγ signaling pathways, which in turn modulate phospholipid biosynthesis and induce neutral lipid synthesis. Collectively, our findings highlight the importance of endogenous ligand-activated PPARγ signaling in human sebocyte biology and suggest that PPARγ might be a promising candidate for the clinical management of SG disorders.Journal of Investigative Dermatology accepted article preview online, 15 October 2013; doi:10.1038/jid.2013.413.