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Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice.

Baker NA, Shoemaker R, English V, Larian N, Sunkara M, Morris AJ, Walker M, Yiannikouris F, Cassis LA - Environ. Health Perspect. (2015)

Bottom Line: The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

ABSTRACT

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.

Objectives: 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.

Methods and 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.

No MeSH data available.


Related in: MedlinePlus

Effect of adipocyte AhR deficiency and PCB-77 on mRNA abundance of AhR (A), Cyp1A1 (B), and Tnf‑alpha (C) in epididymal adipose tissue from mice of each genotype and treatment group following 4 weeks of weight loss. Data are mean ± SE from n = 5 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.
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f6: Effect of adipocyte AhR deficiency and PCB-77 on mRNA abundance of AhR (A), Cyp1A1 (B), and Tnf‑alpha (C) in epididymal adipose tissue from mice of each genotype and treatment group following 4 weeks of weight loss. Data are mean ± SE from n = 5 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.

Mentions: Previous studies demonstrated that administration of PCB-77 during the weight-gain phase of diet-induced obesity had no effect on adipose inflammation or glucose homeostasis, presumably due to sequestration of the lipophilic toxicant in expanded adipose lipids (Baker et al. 2013b). However, when obese mice previously exposed to PCB-77 lost weight, the benefits of weight loss to reduce adipose mRNA abundance of TNF-α and to improve glucose tolerance were mitigated (Baker et al. 2013b). These results suggest that upon weight loss, PCB-77 is released from expanded adipose lipids of obese mice to promote AhR-mediated adipose inflammation and to impair glucose tolerance, blunting beneficial effects of weight loss. We quantified mRNA abundance of AhR, CYP1A1 (as a marker of AhR activation) and TNF-α (as a marker of inflammation) in adipose tissue of obese mice experiencing weight loss (mice were exposed to PCB-77 during the weight-gain phase of diet-induced obesity). In mice administered PCB-77, AhR mRNA abundance in adipose tissue was significantly decreased in AhRAdQ mice compared with AhRfl/fl mice (Figure 6A; p < 0.05). Similarly, in adipose tissue of AhRfl/fl mice administered PCB-77, Cyp1A1 mRNA abundance was markedly increased, indicative of AhR activation (Figure 6B; p < 0.05). In contrast, PCB-77 had no effect on Cyp1A1 mRNA abundance in adipose tissue from mice with adipocyte AhR deficiency. Finally, Tnf-alpha mRNA abundance was significantly increased in adipose tissue of AhRfl/fl mice administered PCB-77 compared with VEH, with no effect of the toxicant on Tnf-alpha mRNA abundance in adipose tissue of AhRAdQ mice (Figure 6C; p < 0.05).


Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice.

Baker NA, Shoemaker R, English V, Larian N, Sunkara M, Morris AJ, Walker M, Yiannikouris F, Cassis LA - Environ. Health Perspect. (2015)

Effect of adipocyte AhR deficiency and PCB-77 on mRNA abundance of AhR (A), Cyp1A1 (B), and Tnf‑alpha (C) in epididymal adipose tissue from mice of each genotype and treatment group following 4 weeks of weight loss. Data are mean ± SE from n = 5 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590748&req=5

f6: Effect of adipocyte AhR deficiency and PCB-77 on mRNA abundance of AhR (A), Cyp1A1 (B), and Tnf‑alpha (C) in epididymal adipose tissue from mice of each genotype and treatment group following 4 weeks of weight loss. Data are mean ± SE from n = 5 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.
Mentions: Previous studies demonstrated that administration of PCB-77 during the weight-gain phase of diet-induced obesity had no effect on adipose inflammation or glucose homeostasis, presumably due to sequestration of the lipophilic toxicant in expanded adipose lipids (Baker et al. 2013b). However, when obese mice previously exposed to PCB-77 lost weight, the benefits of weight loss to reduce adipose mRNA abundance of TNF-α and to improve glucose tolerance were mitigated (Baker et al. 2013b). These results suggest that upon weight loss, PCB-77 is released from expanded adipose lipids of obese mice to promote AhR-mediated adipose inflammation and to impair glucose tolerance, blunting beneficial effects of weight loss. We quantified mRNA abundance of AhR, CYP1A1 (as a marker of AhR activation) and TNF-α (as a marker of inflammation) in adipose tissue of obese mice experiencing weight loss (mice were exposed to PCB-77 during the weight-gain phase of diet-induced obesity). In mice administered PCB-77, AhR mRNA abundance in adipose tissue was significantly decreased in AhRAdQ mice compared with AhRfl/fl mice (Figure 6A; p < 0.05). Similarly, in adipose tissue of AhRfl/fl mice administered PCB-77, Cyp1A1 mRNA abundance was markedly increased, indicative of AhR activation (Figure 6B; p < 0.05). In contrast, PCB-77 had no effect on Cyp1A1 mRNA abundance in adipose tissue from mice with adipocyte AhR deficiency. Finally, Tnf-alpha mRNA abundance was significantly increased in adipose tissue of AhRfl/fl mice administered PCB-77 compared with VEH, with no effect of the toxicant on Tnf-alpha mRNA abundance in adipose tissue of AhRAdQ mice (Figure 6C; p < 0.05).

Bottom Line: The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

ABSTRACT

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.

Objectives: 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.

Methods and 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.

No MeSH data available.


Related in: MedlinePlus