Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice.
BACKGROUND
Coplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss in obese mice. The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.


OBJECTIVE
In this study we tested the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhRs) to promote adipose inflammation and impair glucose homeostasis in lean mice and in obese mice during weight loss.


RESULTS
PCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)-fed control (AhR(fl/fl)) mice but not in adipocyte AhR-deficient mice (AhR(AdQ)). Unexpectedly, AhR(AdQ) mice exhibited increased fat mass when fed a standard LF or high fat (HF) diet. In mice fed a HF diet, both genotypes became obese, but AhR(AdQ) mice administered vehicle (VEH) exhibited increased body weight, adipose mass, adipose inflammation, and impaired glucose tolerance compared with AhR(fl/fl) controls. Impairment of glucose homeostasis in response to PCB-77 was not observed in obese mice of either genotype. However, upon weight loss, AhR(fl/fl) mice administered PCB-77 exhibited increased abundance of adipose tumor necrosis factor-α (TNF-α) mRNA and impaired glucose homeostasis compared with those administered VEH. In contrast, PCB-77 had no effect on TNF-α or glucose homeostasis in AhR(AdQ) mice exhibiting weight loss.


CONCLUSIONS
Our results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice. Moreover, deficiency of AhR in adipocytes augmented the development of obesity, indicating that endogenous ligand(s) for AhR regulate adipose homeostasis.
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
Nicki A
NA
Baker
Robin
R
Shoemaker
Victoria
V
English
Nika
N
Larian
Manjula
M
Sunkara
Andrew J
AJ
Morris
Mary
M
Walker
Frederique
F
Yiannikouris
Lisa A
LA
Cassis
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism*; D015431:Weight Loss
D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; D005947:Glucose; C028451:3,4,3',4'-tetrachlorobiphenyl