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

© 2020 Gordon et al..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:295

Enthalten in:

The Journal of biological chemistry - 295(2020), 29 vom: 17. Juli, Seite 9804-9822

Sprache:

Englisch

Beteiligte Personen:

Gordon, Darren M [VerfasserIn]
Neifer, Kari L [VerfasserIn]
Hamoud, Abdul-Rizaq Ali [VerfasserIn]
Hawk, Charles F [VerfasserIn]
Nestor-Kalinoski, Andrea L [VerfasserIn]
Miruzzi, Scott A [VerfasserIn]
Morran, Michael P [VerfasserIn]
Adeosun, Samuel O [VerfasserIn]
Sarver, Jeffrey G [VerfasserIn]
Erhardt, Paul W [VerfasserIn]
McCullumsmith, Robert E [VerfasserIn]
Stec, David E [VerfasserIn]
Hinds, Terry D [VerfasserIn]

Links:

Volltext

Themen:

Adrb3 protein, mouse
Beige fat
Bilirubin
Biliverdin
Browning
Fatty acid oxidation
Hormone
Journal Article
Nuclear receptor
Obesity
PPARα
PPARγ
PPARδ
PPAR alpha
Peroxisome proliferator‐activated receptor (PPAR)
Peroxisome proliferator-activated receptor (PPAR)
Ppara protein, mouse
RFM9X3LJ49
Receptors, Adrenergic, beta-3
Research Support, N.I.H., Extramural
Ucp1 protein, mouse
Uncoupling Protein 1

Anmerkungen:

Date Completed 14.01.2021

Date Revised 18.07.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1074/jbc.RA120.013700

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM309873320