PCB126 blocks the thermogenic beiging response of adipocytes
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.
KeywordsPCB126 Adipocytes Indoxyl sulfate Fat AhR Diabetes
polychlorinated biphenyl congener 126
uncoupling protein 1
short hairpin RNA
aryl hydrocarbon receptor
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).
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Conflict of interest
The authors declare that they have no conflicts of interest.
- Alexander DL, Ganem LG, Fernandez-Salguero P, Gonzalez F, Jefcoate CR (1998) Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. J Cell Sci 111:3311–3322Google Scholar
- Baker NA, Karounos M, English V, Fang J, Wei Y, Stromberg A, Sunkara M, Morris AJ, Swanson HI, Cassis LA (2013) Coplanar polychlorinated biphenyls impair glucose homeostasis in lean C57BL/6 mice and mitigate beneficial effects of weight loss on glucose homeostasis in obese mice. Environ Health Perspect 121:105–110CrossRefGoogle Scholar
- Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML, Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, Nakamura T, Gilot D, Denison MS, Guillemin GJ, DuHadaway JB, Prendergast GC, Metz R, Geffard M, Boon L, Pirro M, Iorio A, Veyret B, Romani L, Grohmann U, Fallarino F, Puccetti P (2014) Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511:184–190CrossRefGoogle Scholar
- Biljes D, Hammerschmidt-Kamper C, Kadow S, Diel P, Weigt C, Burkart V, Esser C (2015) Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice. EXCLI J 14:1153–1163Google Scholar
- Kerley-Hamilton JS, Trask HW, Ridley CJ, Dufour E, Ringelberg CS, Nurinova N, Wong D, Moodie KL, Shipman SL, Moore JH, Korc M, Shworak NW, Tomlinson CR (2012) Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet. Environ Health Perspect 120:1252–1259CrossRefGoogle Scholar
- Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, Lee TG, Kang JK, Gasiewicz TA, Ryu SH, Suh PG (2006) Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol 69:1871–1878CrossRefGoogle Scholar
- Littlejohn NK, Keen HL, Weidemann BJ, Claflin KE, Tobin KV, Markan KR, Park S, Naber MC, Gourronc FA, Pearson NA, Liu X, Morgan DA, Klingelhutz AJ, Potthoff MJ, Rahmouni K, Sigmund CD, Grobe JL (2016) Suppression of resting metabolism by the angiotensin AT2 receptor. Cell Rep 16:1548–1560CrossRefGoogle Scholar
- Patel P, Abate N (2013b) Role of subcutaneous adipose tissue in the pathogenesis of insulin resistance. J Obes 2013:489187Google Scholar
- Perkins A, Phillips JL, Kerkvliet NI, Tanguay RL, Perdew GH, Kolluri SK, Bisson WH (2014) A structural switch between agonist and antagonist bound conformations for a ligand-optimized model of the human aryl hydrocarbon receptor ligand binding domain. Biology (Basel) 3:645–669Google Scholar
- Phillips M, Enan E, Liu PC, Matsumura F (1995) Inhibition of 3 T3-L1 adipose differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Cell Sci 108:395–402Google Scholar
- Ruzzin J, Petersen R, Meugnier E, Madsen L, Lock EJ, Lillefosse H, Ma T, Pesenti S, Sonne SB, Marstrand TT, Malde MK, Du ZY, Chavey C, Fajas L, Lundebye AK, Brand CL, Vidal H, Kristiansen K, Froyland L (2010) Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect 118:465–471CrossRefGoogle Scholar
- Wada T, Sunaga H, Miyata K, Shirasaki H, Uchiyama Y, Shimba S (2016) Aryl hydrocarbon receptor plays protective roles against high fat diet (HFD)-induced hepatic steatosis and the subsequent lipotoxicity via direct transcriptional regulation of socs3 gene expression. J Biol Chem 291:7004–7016CrossRefGoogle Scholar