Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor a

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator-activated receptor a (PPARa). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARa target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor b 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARa and does not affect the activities of the related proteins PPARg and PPARd. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARa-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARa coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.