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 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.
Original language | English |
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Pages (from-to) | 9804-9822 |
Number of pages | 19 |
Journal | Journal of Biological Chemistry |
Volume | 295 |
Issue number | 29 |
DOIs | |
State | Published - Jul 17 2020 |
Bibliographical note
Publisher Copyright:© 2020 Gordon et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
Funding
We thank Rene Houtman with PamGene (Netherlands) and the PamGene team for helpful discussions and assistance in developing protocols to use the PamStation NHR chip technology for white adipose tissue from mice. We also thank John M. Rimoldi, Rama S. Gadepalli, and the Research Institute of Pharmaceutical Sciences at the University of Mississippi (Oxford, MS, USA) for the synthesis of pegylated bilirubin used in the studies. We also acknowledge the Analytical and Assay Core in the Department of Physiology and Biophysics at the University of Mississippi Medical Center. Funding and additional information-This work was supported by the National Institutes of Health (NIH) Grants 1R01DK121797-01A1 (to D. E. S.) and 1R01DK126884-01 (to D. E. S. and T. D. H.); NHLBI, NIH, Grants K01HL-125445 (to T. D. H.) and P01 HL05197-11 (to D. E. S.); and NIGMS, National Institutes of Health, Grant P20GM104357-02 (to D. E. S.). This project was supported in part by Grant P30GM122733 (Chemistry and DMPK Core Faculty) funded by NIGMS (NIH) as one of its Centers of Biomedical Research Excellence (COBRE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding and additional information\u2014This work was supported by the National Institutes of Health (NIH) Grants 1R01DK121797-01A1 (to D. E. S.) and 1R01DK126884-01 (to D. E. S. and T. D. H.); NHLBI, NIH, Grants K01HL-125445 (to T. D. H.) and P01 HL05197-11 (to D. E. S.); and NIGMS, National Institutes of Health, Grant P20GM104357-02 (to D. E. S.). This project was supported in part by Grant P30GM122733 (Chemistry and DMPK Core Faculty) funded by NIGMS (NIH) as one of its Centers of Biomedical Research Excellence (COBRE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funders | Funder number |
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University of Mississippi Medical Center | |
Mississippi Agricultural and Forestry Experiment Station, Mississippi State University | |
National Institute of GeneralMedical Sciences Centers of Biomedical Research Excellence | |
Delhi Institute of Pharmaceutical Sciences and Research | |
National Heart, Lung, and Blood Institute (NHLBI) | P01 HL05197-11, K01HL-125445 |
National Heart, Lung, and Blood Institute (NHLBI) | |
National Institutes of Health (NIH) | 1R01DK121797-01A1, 1R01DK126884-01 |
National Institutes of Health (NIH) | |
National Institute of General Medical Sciences | P20GM104357-02, P30GM122733 |
National Institute of General Medical Sciences |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology