Inducible Loss of the Aryl Hydrocarbon Receptor Activates Perigonadal White Fat Respiration and Brown Fat Thermogenesis via Fibroblast Growth Factor 21

International Journal of Molecular Sciences
Nathaniel G GirerCornelis J Elferink

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models can complicate efforts to distinguish the direct and indirect effects of post-gestational AHR deficiency. Utilizing a novel tamoxifen-inducible AHR knockout mouse model, we analyzed the effects of hepatocyte-targeted AHR loss in adult mice. The data demonstrate that AHR deficiency significantly reduces weight gain and adiposity, and increases multilocular lipid droplet formation within perigonadal white adipose tissue (gWAT). Protein and mRNA expression of fibroblast growth factor 21 (FGF21), an important hepatokine that activates thermogenesis in brown adipose tissue (BAT) and gWAT, significantly increases upon AHR loss and correlates with a significant increase of BAT and gWAT respiratory capacity. Confirming the role of FGF21 in mediating these effects, this phenotype is reversed in mice concomitantly lacking AHR and FGF21 expression. Chromatin immunoprecipitation analyses suggest that the AHR may constitutively supp...Continue Reading

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Citations

Jun 26, 2020·Journal of Cellular Physiology·Chang GuoGuoyue Yuan
Jan 9, 2020·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Itzel Y RojasCraig R Tomlinson
Mar 3, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ashlee E WilliamsMartin J J Ronis
Dec 31, 2020·International Journal of Molecular Sciences·Nathaniel G GirerCornelis J Elferink

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Methods Mentioned

BETA
ELISA
immunoprecipitation
targeted mutations

Software Mentioned

Graphpad Prism
Skyline
cuffdiff
GenStat
cufflink
MacCoss
tophat
ExPASy
ZEN
R

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