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PPARγ and PPARα synergize to induce robust browning of white fat in vivo
- Source :
- Molecular Metabolism, Molecular Metabolism, Vol 36, Iss, Pp-(2020)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- Objective Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat. Methods A selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice. Results All dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. Conclusions PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21.<br />Graphical abstract Dual PPARα/γ activation is superior to selective PPARγ activation at inducing browning of white fat in vivo: via PPARγ action in the adipose and a PPARα-mediated action in the liver resulting in increased circulating fibroblast growth factor 21 (FGF21).Image 1<br />Highlights • Dual PPARα/γ activators robustly induce browning of white fat in vitro and in vivo. • PPARγ action alone is sufficient to convert white into brown-like adipocytes in vitro. • Dual PPARα/γ activators are superior to PPARγ activators for browning of white fat in vivo. • PPARγ action in adipose and PPARα-mediated increase in FGF21 synergize to induce browning of white fat in vivo.
- Subjects :
- 0301 basic medicine
Male
FGF21
Adipocytes, White
Peroxisome proliferator-activated receptor
Adipose tissue
FGF21, fibroblast growth factor 21
White adipose tissue
PPAR
chemistry.chemical_compound
Mice
0302 clinical medicine
iWAT, inguinal WAT
Adipose Tissue, Brown
iBAT, interscapular BAT
Uncoupling Protein 1
chemistry.chemical_classification
Brown adipocytes
Thermogenesis
WAT, white adipose tissue
TG, triglycerides
TN, thermoneutrality
Thermogenin
DIO, diet-induced obese
Adipocytes, Brown
RT, room temperature
Original Article
TZD, thiazolidinedione
Rosiglitazone
medicine.drug
medicine.medical_specialty
lcsh:Internal medicine
UCP1
Tesaglitazar
Adipose Tissue, White
030209 endocrinology & metabolism
QUICKI, quantitative insulin-sensitivity check index
eWAT, epididymal WAT
PPAR, peroxisome proliferator-activated receptors
03 medical and health sciences
Beige adipocytes
Internal medicine
UCP1, uncoupling protein 1
medicine
Animals
PPAR alpha
lcsh:RC31-1245
Molecular Biology
Activator (genetics)
EE, energy expenditure
Cell Biology
BAT, brown adipose tissue
Mice, Inbred C57BL
PPAR gamma
030104 developmental biology
Endocrinology
chemistry
Energy Metabolism
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 22128778
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Molecular Metabolism
- Accession number :
- edsair.doi.dedup.....2c62ccf8173db31d2d6e27df33b3b3fd