Journal article
Pdgfrα-Cre mediated knockout of the aryl hydrocarbon receptor protects mice from high-fat diet induced obesity and hepatic steatosis
PloS one, Vol.15(7), pp.e0236741-e0236741
07/01/2020
DOI: 10.1371/journal.pone.0236741
PMCID: PMC7392206
PMID: 32730300
Abstract
Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes
in vitro
. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR’s role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahr
fl/fl
) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahr
fl/fl
mice (control mice). The Pdgfrα-Cre Ahr
fl/fl
knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahr
fl/fl
mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.
Details
- Title: Subtitle
- Pdgfrα-Cre mediated knockout of the aryl hydrocarbon receptor protects mice from high-fat diet induced obesity and hepatic steatosis
- Creators
- Francoise A GourroncKathleen R MarkanKatarina KulhankovaZhiyong ZhuRyan SheehyDawn E QuelleLeonid V ZingmanZoya B KuragoJames A AnkrumAloysius J Klingelhutz
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.15(7), pp.e0236741-e0236741
- DOI
- 10.1371/journal.pone.0236741
- PMID
- 32730300
- PMCID
- PMC7392206
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; San Francisco, CA USA
- Grant note
- ; K01DK111758 / ;
- Alternative title
- Aryl hydrocarbon receptor knockout by Pdgfrα-Cre protects mice from obesity
- Language
- English
- Date published
- 07/01/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Radiation Oncology; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984001094002771
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