Shared PPARα/γ Target Genes Regulate Brown Adipocyte Thermogenic Function

Abstract

Summary: Brown adipose tissue (BAT) generates heat to maintain body temperature and suppress obesity. Agonists for nuclear receptors PPARα and PPARγ both affect brown adipocyte function, yet the interplay between these factors in BAT is uncertain. Here, we report that PPARα shares most genomic binding sites with PPARγ, and these common binding sites are more related to BAT function than PPARγ-selective sites without PPARα. Integrating PPARα and PPARγ 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 PPARα/γ target gene in BAT and a regulator of brown adipocyte thermogenic function. : Brown adipocytes uniquely express high levels of PPARα and PPARγ, yet the interplay between these two nuclear receptors was unknown. Shen et al. show PPARα co-occupies regulatory DNA with PPARγ. Shared target genes of both, including the candidate CTSZ, reveal brown fat function better than PPARγ targets alone. Keywords: brown adipocytes, PPARα, PPARγ, rosiglitazone, fenofibrate, CTSZ, thermogenesis