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


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 alpha (PPARalpha). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARalpha target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor beta 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARalpha and does not affect the activities of the related proteins PPARgamma and PPARdelta. 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 PPARalpha-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARalpha coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.