Shared PPARα/γ Target Genes Regulate Brown Adipocyte Thermogenic Function

Brown adipose tissue (BAT) generates heat to maintain body temperature and suppress obesity. Agonists for nuclear receptors PPAR alpha and PPAR gamma both affect brown adipocyte function, yet the interplay between these factors in BAT is uncertain. Here, we report that PPAR alpha shares most genomic binding sites with PPAR gamma, and these common binding sites are more related to BAT function than PPAR gamma-selective sites without PPAR alpha. Integrating PPAR alpha and PPAR gamma genomic occupancy with cold-responsive BAT transcriptomes identifies a subset of 16 genes with potential relevance to BAT function. Among these, we focused on the lysosomal protease cathepsin Z (CTSZ) and showed it is necessary for mitochondrial respiration in both mouse and human brown adipocytes. Thus, CTSZ is a shared PPAR alpha/gamma target gene in BAT and a regulator of brown adipocyte thermogenic function.