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PCB126 blocks the thermogenic beiging response of adipocytes

  • Francoise A. Gourronc
  • Gary H. Perdew
  • Larry W. Robertson
  • Aloysius J. KlingelhutzEmail author
Fifty Years of PCB Research: New Approaches and Discoveries and still so much more to learn

Abstract

Subcutaneous white adipose tissue is capable of becoming thermogenic in a process that is referred to as “beiging.” Beiging is associated with activation of the uncoupling protein, UCP1, and is known to be important for preventing adipose hypertrophy and development of insulin resistance. Polychlorinated biphenyls (PCBs) accumulate in fat, and it is hypothesized that disruption of adipogenesis and adipocyte function by PCBs may be causative in the development of obesity and diabetes. We developed immortal human subcutaneous preadipocytes that, when differentiated, are capable of beiging. Preadipocytes that were treated with polychlorinated biphenyl congener 126 (PCB126), followed by differentiation, were suppressed for their ability to activate UCP1 upon β-adrenergic stimulation with norepinephrine (NE), demonstrating a block in the beiging response. Treatment of preadipocytes with another known endogenous AhR agonist, indoxyl sulfate (IS), followed by differentiation also blocked the NE-stimulated upregulation of UCP1. Knockdown of the aryl hydrocarbon receptor (AhR) caused the preadipocytes to be refractory to PCB126 and IS effects. The chemical AhR antagonist, CH223191, was effective at preventing the effects of PCB126 but not IS, indicating AhR ligand specificity of CH223191. Repression of NE-induced UCP1 upregulation was also observed when already-differentiated mature adipocytes were treated with PCB126 but not IS. These results indicate that exposure of preadipocytes to endogenous (IS) or exogenous (PCB126) AhR agonists is effective at blocking them from becoming functional adipocytes that are capable of the beiging response. Mature adipocytes may have differential responses. This finding suggests a mechanism by which dioxin-like PCBs such as PCB126 could lead to disruption in energy homeostasis, potentially leading to obesity and diabetes.

Keywords

PCB126 Adipocytes Indoxyl sulfate Fat AhR Diabetes 

Abbreviations

PCB126

polychlorinated biphenyl congener 126

UCP1

uncoupling protein 1

NPAD

normal preadipocytes

shRNA

short hairpin RNA

AhR

aryl hydrocarbon receptor

IS

indoxyl sulfate

Notes

Acknowledgments

We thank Dr. Hans Joachim-Lehmler of the Iowa Superfund Research Program (P42 ES013661) for PCB126. Quantitative RT–PCR was performed at the University of Iowa Genomics Facility. This work was supported by a pilot grant from the University of Iowa Environmental Health Sciences Research Center (grant number P30 ES05605) to AJK, a University of Iowa Fraternal Order of Eagles Diabetes Research Center Award given to AJK, an NIH grant to GHP (R01 ES004869), and the Iowa Superfund Research Program Grant (P42 ES013661) to LWR. The qRT–PCR data were obtained at the Genomics Division of the Iowa Institute of Human Genetics which is supported, in part, by the University of Iowa Carver College of Medicine and the Holden Comprehensive Cancer Center (National Cancer Institute of the National Institutes of Health under Award Number P30 CA086862).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyUniversity of IowaIowa CityUSA
  2. 2.Center for Molecular Toxicology and Carcinogenesis and the Department of Veterinary and Biomedical SciencesPennsylvania State UniversityUniversity ParkUSA
  3. 3.Department of Occupational & Environmental Health, College of Public HealthUniversity of IowaIowa CityUSA

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