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Molecular Biology

Reversal of obesity and liver steatosis in mice via inhibition of aryl hydrocarbon receptor and altered gene expression of CYP1B1, PPARα, SCD1, and osteopontin

Abstract

Background/objectives

Obesity is a global epidemic and the underlying basis for numerous comorbidities. We report that the aryl hydrocarbon receptor (AHR) plays a key role in the metabolism of obesity. The AHR is a promiscuous, ligand-activated nuclear receptor primarily known for regulating genes involved in xenobiotic metabolism and T cell polarization. The aims of the work reported here were to understand the underlying mechanism of AHR-based obesity and to determine whether inhibition of AHR activity would reverse obesity.

Methods

Mice were fed control (low fat) and Western (high fat) diets with and without the AHR antagonist alpha-naphthoflavone (aNF). Gene expression of identified AHR-regulated genes from liver and adipose tissue was characterized. To determine the role of the AHR in obesity reversal, selected mice in control and Western diet regimens were switched at midpoint to the respective control and Western diets containing aNF, and the identified AHR-regulated genes characterized.

Results

AHR inhibition prevented obesity in mice on a 40-week diet regimen. The likely AHR-regulated and cross-regulated downstream effectors of AHR-based obesity were shown to be CYP1B1, PPARα-target genes, SCD1, and SPP1 (osteopontin). Western diet caused an increase of mRNA and protein expression of the Cyp1b1, Scd1, and Spp1, and PPARα-target genes in the liver, and inhibition of the AHR maintained expression of these genes near control levels. The body weight of obese mice on Western diet switched to Western diet containing aNF decreased to that of mice on control diet concurrently with a reduction in the expression of liver CYP1B1, PPARα-target genes, SCD1, and SPP1. AHR inhibition prevented hypertrophy and hyperplasia in visceral adipose tissue and limited expression levels of CYP1B1 and SPP1 to that of mice on control diet.

Conclusions

AHR inhibition prevents and reverses obesity by likely reducing liver expression of the Cyp1b1, Scd1, Spp1, and PPARα-target genes; and the AHR is a potentially potent therapeutic target for the treatment and prevention of obesity and linked diseases.

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Fig. 1: Expression of liver CYP1B1 in AHR-based obesity.
Fig. 2: AHR inhibition decreases protein expression of liver PPARα target genes.
Fig. 3: AHR inhibition represses Scd1 expression and plasma arachidonic acid concentrations.
Fig. 4: Inhibition of AHR signaling decreases SPP1 expression and secretion.
Fig. 5: The AHR antagonist aNF reverses Western diet-induced obesity in male B6 mice.
Fig. 6: Model depicting AHR-based obesity in liver.

Data availability

Any data and materials not in the public domain that were generated from these reported studies will be made available upon request.

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Acknowledgements

We thank the editors and reviewers for their thoughtful comments. The authors acknowledge the following core facilities: Genomics & Molecular Biology Shared Resource, Clinical Pharmacology Shared Resource, Irradiation, Pre-clinical Imaging & Microscopy Shared Resource, and Pathology Shared Resource at the Norris Cotton Cancer Center at Dartmouth with NCI Cancer Center Support Grant 5P30CA023108-40.

Funding

This work was supported by funding from NCI 5P30CA023108-40, NIH-NCRR award 5P20RR024475-02, NIH-NIGMS award 8P20GM103534-02, and a NCCC Prouty Pilot Award.

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IYR, BJM, and CRT conceived and designed the studies. IYR, CSR, and BJM performed the experiments and acquired the data. IYR, CSR, and CRT ran the computations and analyzed the data. IYR and CRT wrote and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Craig R. Tomlinson.

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The studies with mice (Mus musculus) were conducted using an animal protocol approved by the Dartmouth Hitchcock Medical Center Institutional Animal Care and Use Committee, IACUC PROTOCOL NUMBER toml.cr.1#2(m5ar5), ASSURANCE NUMBER A3259-01.

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Rojas, I.Y., Moyer, B.J., Ringelberg, C.S. et al. Reversal of obesity and liver steatosis in mice via inhibition of aryl hydrocarbon receptor and altered gene expression of CYP1B1, PPARα, SCD1, and osteopontin. Int J Obes 44, 948–963 (2020). https://doi.org/10.1038/s41366-019-0512-z

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