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

Authors
  • Girer, Nathaniel G1
  • Carter, Dwayne2
  • Bhattarai, Nisha3, 4
  • Mustafa, Mehnaz5
  • Denner, Larry6
  • Porter, Craig7
  • Elferink, Cornelis J8
  • 1 Department of Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 2 Department of Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 3 Division of Surgical Sciences, Department of Surgery, UTMB & Metabolism Unit, Shriners Hospitals for Children, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 4 Division of Rehabilitation Sciences, School of Health Professions, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 5 Department of Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 6 Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 7 Division of Surgical Sciences, Department of Surgery, UTMB & Metabolism Unit, Shriners Hospitals for Children, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
  • 8 Department of Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected]
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Feb 22, 2019
Volume
20
Issue
4
Identifiers
DOI: 10.3390/ijms20040950
PMID: 30813227
Source
Medline
Keywords
Language
English
License
Unknown

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 suppress Fgf21 transcription through binding to a newly identified xenobiotic response element within the Fgf21 promoter. The data demonstrate an important AHR-FGF21 regulatory axis that influences adipose biology and may represent a "druggable" therapeutic target for obesity and its related metabolic disorders.

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