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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.Our results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice.

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 on insulin tolerance in lean mice administered PCB-77. (A) Blood glucose concentrations following administration of insulin in mice of each genotype administered VEH or PCB-77 (week 3). Data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment. (B) Area under the curve (AUC) for data in (A). Data are mean ± SE from n = 6–8 mice/group. *p < 0.05 compared with AhRfl/fl within treatment. **p < 0.05 compared with VEH within genotype.
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f2: Effect of adipocyte AhR deficiency on insulin tolerance in lean mice administered PCB-77. (A) Blood glucose concentrations following administration of insulin in mice of each genotype administered VEH or PCB-77 (week 3). Data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment. (B) Area under the curve (AUC) for data in (A). Data are mean ± SE from n = 6–8 mice/group. *p < 0.05 compared with AhRfl/fl within treatment. **p < 0.05 compared with VEH within genotype.

Mentions: Effect of adipocyte AhR deficiency on insulin tolerance in lean mice acutely exposed to PCB-77. We previously demonstrated that lean mice exposed to four divided doses of PCB-77 develop impaired insulin tolerance within 48 hr after the last dose (Baker et al. 2013b). Thus, we defined effects of adipocyte AhR deficiency on acute PCB-77–induced dysregulation of insulin tolerance in mice fed an LF diet (Figure 2A,B). Body weights were not significantly different between groups at the study end point (AhRfl/fl VEH, 28.1 ± 0.5; AhRfl/fl PCB-77, 27.9 ± 0.5; AhRAdQ VEH, 25.5 ± 0.5; AhRAdQ PCB-77, 27.1 ± 0.5 g; p > 0.05). Compared with AhRfl/fl VEH mice, AhRAdQ VEH mice showed a modest, but significant, improvement in insulin tolerance, as indicated by a significant reduction in blood glucose concentrations at 90 and 120 min after insulin administration and by a significant reduction in the AUC (Figure 2A,B; p < 0.05). Notably, administration of PCB-77 significantly impaired insulin tolerance in AhRfl/fl but not in AhRAdQ mice (Figure 2A,B; 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 on insulin tolerance in lean mice administered PCB-77. (A) Blood glucose concentrations following administration of insulin in mice of each genotype administered VEH or PCB-77 (week 3). Data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment. (B) Area under the curve (AUC) for data in (A). Data are mean ± SE from n = 6–8 mice/group. *p < 0.05 compared with AhRfl/fl within treatment. **p < 0.05 compared with VEH within genotype.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f2: Effect of adipocyte AhR deficiency on insulin tolerance in lean mice administered PCB-77. (A) Blood glucose concentrations following administration of insulin in mice of each genotype administered VEH or PCB-77 (week 3). Data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment. (B) Area under the curve (AUC) for data in (A). Data are mean ± SE from n = 6–8 mice/group. *p < 0.05 compared with AhRfl/fl within treatment. **p < 0.05 compared with VEH within genotype.
Mentions: Effect of adipocyte AhR deficiency on insulin tolerance in lean mice acutely exposed to PCB-77. We previously demonstrated that lean mice exposed to four divided doses of PCB-77 develop impaired insulin tolerance within 48 hr after the last dose (Baker et al. 2013b). Thus, we defined effects of adipocyte AhR deficiency on acute PCB-77–induced dysregulation of insulin tolerance in mice fed an LF diet (Figure 2A,B). Body weights were not significantly different between groups at the study end point (AhRfl/fl VEH, 28.1 ± 0.5; AhRfl/fl PCB-77, 27.9 ± 0.5; AhRAdQ VEH, 25.5 ± 0.5; AhRAdQ PCB-77, 27.1 ± 0.5 g; p > 0.05). Compared with AhRfl/fl VEH mice, AhRAdQ VEH mice showed a modest, but significant, improvement in insulin tolerance, as indicated by a significant reduction in blood glucose concentrations at 90 and 120 min after insulin administration and by a significant reduction in the AUC (Figure 2A,B; p < 0.05). Notably, administration of PCB-77 significantly impaired insulin tolerance in AhRfl/fl but not in AhRAdQ mice (Figure 2A,B; 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.Our results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice.

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