PPARγ and PPARα synergize to induce robust browning of white fat in vivo

• 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. © 2020 The Authors

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Beige adipocytes

Brown adipocytes

FGF21

PPAR

Thermogenesis

UCP1

aleglitazar

chiglitazar

fatty acid binding protein 4

fenofibrate

fibroblast growth factor 21

imiglitazar

insulin

messenger RNA

muraglitazar

neutral insulin

peroxisome proliferator activated receptor alpha

peroxisome proliferator activated receptor gamma

pirinixic acid

ragaglitazar

reglitazar

rosiglitazone

saroglitazar

tesaglitazar

uncoupling protein 1

animal cell

animal experiment

animal model

animal tissue

Article

body weight loss

brown adipocyte

brown adipose tissue

Cidea gene

controlled study

drug dose comparison

drug mechanism

drug megadose

Ehhadh gene

energy expenditure

Fabp4 gene

fatty liver

female

gene

gene expression

high-fat diet-induced fatty liver

human

human cell

in vitro study

in vivo study

insulin sensitivity

lean body weight

low drug dose

male

mouse

nonhuman

obesity

Pdk4 gene

priority journal

proadipocyte

protein blood level

protein expression

protein function

Ucp1 gene

white adipocyte

white adipose tissue

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