Abstract
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 α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. 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 PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.
Highlights
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
The benefit of the Gal4 system is that endogenous peroxisome proliferator-activated receptor (PPAR) are not responsive to the promoter, and only molecules that bind to the ligand-binding domain (LBD) drive expression
The Gal4-hPPARa-LBD responded to increasing bilirubin levels at the Gal4-driven upstream activation sequence (UAS) promoter (Fig. 1A, left)
Summary
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. Activation of the browning of WAT, increasing energy expenditure and boosting the burning of fat, has significant implications in reducing adiposity and insulin resistance [14,15,16]. These processes are mediated by mitochondrial uncoupling proteins during physical activity or brown fat–mediated thermogenesis. The latter may be a potent inducer of some activities with reduced unwanted effects
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