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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 on PCB-77-induced impairment of glucose and insulin tolerance in obese mice exhibiting weight loss. After 12 weeks of HF feeding, mice of each genotype and treatment group were switched to an LF diet for 4 weeks to induce weight loss. (A) Blood glucose concentrations following a bolus of i.p.-administered glucose in mice of each genotype and treatment group following 4 weeks of weight loss. (B) Blood glucose concentrations following a bolus of i.p.-administered insulin in mice of each genotype and treatment group. For (A) and (B), *p < 0.05 compared with AhRfl/fl within treatment group. (C) Area under the curve (AUC) for data in (A) and (D) AUC for data in (B); data are mean ± SE from n = 6–8 mice/genotype/treatment group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.
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f5: Effect of adipocyte AhR deficiency on PCB-77-induced impairment of glucose and insulin tolerance in obese mice exhibiting weight loss. After 12 weeks of HF feeding, mice of each genotype and treatment group were switched to an LF diet for 4 weeks to induce weight loss. (A) Blood glucose concentrations following a bolus of i.p.-administered glucose in mice of each genotype and treatment group following 4 weeks of weight loss. (B) Blood glucose concentrations following a bolus of i.p.-administered insulin in mice of each genotype and treatment group. For (A) and (B), *p < 0.05 compared with AhRfl/fl within treatment group. (C) Area under the curve (AUC) for data in (A) and (D) AUC for data in (B); data are mean ± SE from n = 6–8 mice/genotype/treatment group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.

Mentions: As we demonstrated previously (Baker et al. 2013b), after weight loss AhRfl/fl PCB-77 mice exhibited significantly impaired glucose and insulin tolerance compared with AhRfl/fl VEH mice (Figure 5A–D; p < 0.05). In contrast, PCB-77 had no effect on glucose or insulin tolerance in AhRAdQ mice experiencing weight loss. In response to weight loss, concentrations of PCB-77 in adipose tissue decreased significantly in both genotypes (see Supplemental Material, Figure S3B; p < 0.05). Although concentrations of hydroxy-PCB-77 increased in adipose tissue of both genotypes of mice after experiencing weight loss, levels of the PCB metabolite were significantly decreased in adipose tissue from AhRAdQ mice compared with AhRfl/fl controls (see Supplemental Material, Figure S3C; 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 PCB-77-induced impairment of glucose and insulin tolerance in obese mice exhibiting weight loss. After 12 weeks of HF feeding, mice of each genotype and treatment group were switched to an LF diet for 4 weeks to induce weight loss. (A) Blood glucose concentrations following a bolus of i.p.-administered glucose in mice of each genotype and treatment group following 4 weeks of weight loss. (B) Blood glucose concentrations following a bolus of i.p.-administered insulin in mice of each genotype and treatment group. For (A) and (B), *p < 0.05 compared with AhRfl/fl within treatment group. (C) Area under the curve (AUC) for data in (A) and (D) AUC for data in (B); data are mean ± SE from n = 6–8 mice/genotype/treatment 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

f5: Effect of adipocyte AhR deficiency on PCB-77-induced impairment of glucose and insulin tolerance in obese mice exhibiting weight loss. After 12 weeks of HF feeding, mice of each genotype and treatment group were switched to an LF diet for 4 weeks to induce weight loss. (A) Blood glucose concentrations following a bolus of i.p.-administered glucose in mice of each genotype and treatment group following 4 weeks of weight loss. (B) Blood glucose concentrations following a bolus of i.p.-administered insulin in mice of each genotype and treatment group. For (A) and (B), *p < 0.05 compared with AhRfl/fl within treatment group. (C) Area under the curve (AUC) for data in (A) and (D) AUC for data in (B); data are mean ± SE from n = 6–8 mice/genotype/treatment group.*p < 0.05 compared with VEH within genotype. **p < 0.05 compared with AhRfl/fl within treatment group.
Mentions: As we demonstrated previously (Baker et al. 2013b), after weight loss AhRfl/fl PCB-77 mice exhibited significantly impaired glucose and insulin tolerance compared with AhRfl/fl VEH mice (Figure 5A–D; p < 0.05). In contrast, PCB-77 had no effect on glucose or insulin tolerance in AhRAdQ mice experiencing weight loss. In response to weight loss, concentrations of PCB-77 in adipose tissue decreased significantly in both genotypes (see Supplemental Material, Figure S3B; p < 0.05). Although concentrations of hydroxy-PCB-77 increased in adipose tissue of both genotypes of mice after experiencing weight loss, levels of the PCB metabolite were significantly decreased in adipose tissue from AhRAdQ mice compared with AhRfl/fl controls (see Supplemental Material, Figure S3C; 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