Limits...
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 the development of obesity and increased adiposity in mice fed the HF diet for 12 weeks. (A) Body weights of mice by treatment group and genotype during the 12 weeks of HF feeding; data are mean ± SE from n = 6–8 mice/treatment/genotype. *p < 0.05 compared with AhRfl/fl within treatment. (B) Lean mass and fat mass as a percentage of body weight; data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with AhRfl/fl within treatment group. **p < 0.05 compared with VEH within genotype. (C) A representative mouse from each genotype. (D) Subcutaneous adipose tissue removed from representative AhRfl/fl (left) and AhRAdQ (right) mice (n = 2/group).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4590748&req=5

f3: Effect of adipocyte AhR deficiency on the development of obesity and increased adiposity in mice fed the HF diet for 12 weeks. (A) Body weights of mice by treatment group and genotype during the 12 weeks of HF feeding; data are mean ± SE from n = 6–8 mice/treatment/genotype. *p < 0.05 compared with AhRfl/fl within treatment. (B) Lean mass and fat mass as a percentage of body weight; data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with AhRfl/fl within treatment group. **p < 0.05 compared with VEH within genotype. (C) A representative mouse from each genotype. (D) Subcutaneous adipose tissue removed from representative AhRfl/fl (left) and AhRAdQ (right) mice (n = 2/group).

Mentions: Effect of adipocyte AhR deficiency on the development of obesity, body fat distribution, and glucose homeostasis. Because obesity has been reported to increase the total body burden of lipophilic PCBs (Brown and Lawton 1984; Fukano and Doguchi 1977; McFarland and Clarke 1989), we examined effects of adipocyte AhR deficiency on the development of HF diet–induced obesity and glucose homeostasis in mice of each genotype administered VEH or PCB-77. When challenged with an HF diet, adipocyte AhR–deficient AhRAdQ mice administered VEH had significantly increased body weights, reduced lean mass, and increased fat mass compared with AhRfl/fl controls (Figure 3A–C; p < 0.05). Moreover, excess adiposity in HF-fed AhRAdQ mice administered VEH was deposited subcutaneously, with significant increases in SubQ tissue mass (AhRfl/fl, 3.8 ± 0.5; AhRAdQ, 5.5 ± 0.4; p < 0.05; representative images in Figure 3D) and adipocyte size compared with AhRfl/fl controls (Figure 4A,B). However, these effects were not observed in AhRAdQ mice administered PCB-77 (Figure 4A). Moreover, in mice administered VEH, mRNA abundance of F4/80, a macrophage marker, was significantly increased in EF tissue of AhRAdQ mice compared with AhRfl/fl controls, regardless of treatment group (VEH groups: AhRfl/fl, 1.62 ± 0.67; AhRAdQ, 3.52 ± 0.68; p < 0.05; PCB-77 groups: AhRfl/fl, 1.29 ± 0.49; AhRAdQ, 2.12 ± 0.68 ΔΔCt; p < 0.05). In liver or soleus muscle from HF-fed mice administered VEH, there was no significant effect of genotype on AhR mRNA abundance (see Supplemental Material, Figure S2; p = 0.06). However, administration of PCB-77 resulted in a significant increase in AhR mRNA abundance in liver but not in soleus muscle from HF-fed mice of each genotype, with no significant differences between genotypes (see Supplemental Material, Figure S2; 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 the development of obesity and increased adiposity in mice fed the HF diet for 12 weeks. (A) Body weights of mice by treatment group and genotype during the 12 weeks of HF feeding; data are mean ± SE from n = 6–8 mice/treatment/genotype. *p < 0.05 compared with AhRfl/fl within treatment. (B) Lean mass and fat mass as a percentage of body weight; data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with AhRfl/fl within treatment group. **p < 0.05 compared with VEH within genotype. (C) A representative mouse from each genotype. (D) Subcutaneous adipose tissue removed from representative AhRfl/fl (left) and AhRAdQ (right) mice (n = 2/group).
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f3: Effect of adipocyte AhR deficiency on the development of obesity and increased adiposity in mice fed the HF diet for 12 weeks. (A) Body weights of mice by treatment group and genotype during the 12 weeks of HF feeding; data are mean ± SE from n = 6–8 mice/treatment/genotype. *p < 0.05 compared with AhRfl/fl within treatment. (B) Lean mass and fat mass as a percentage of body weight; data are mean ± SE from n = 6–8 mice/group.*p < 0.05 compared with AhRfl/fl within treatment group. **p < 0.05 compared with VEH within genotype. (C) A representative mouse from each genotype. (D) Subcutaneous adipose tissue removed from representative AhRfl/fl (left) and AhRAdQ (right) mice (n = 2/group).
Mentions: Effect of adipocyte AhR deficiency on the development of obesity, body fat distribution, and glucose homeostasis. Because obesity has been reported to increase the total body burden of lipophilic PCBs (Brown and Lawton 1984; Fukano and Doguchi 1977; McFarland and Clarke 1989), we examined effects of adipocyte AhR deficiency on the development of HF diet–induced obesity and glucose homeostasis in mice of each genotype administered VEH or PCB-77. When challenged with an HF diet, adipocyte AhR–deficient AhRAdQ mice administered VEH had significantly increased body weights, reduced lean mass, and increased fat mass compared with AhRfl/fl controls (Figure 3A–C; p < 0.05). Moreover, excess adiposity in HF-fed AhRAdQ mice administered VEH was deposited subcutaneously, with significant increases in SubQ tissue mass (AhRfl/fl, 3.8 ± 0.5; AhRAdQ, 5.5 ± 0.4; p < 0.05; representative images in Figure 3D) and adipocyte size compared with AhRfl/fl controls (Figure 4A,B). However, these effects were not observed in AhRAdQ mice administered PCB-77 (Figure 4A). Moreover, in mice administered VEH, mRNA abundance of F4/80, a macrophage marker, was significantly increased in EF tissue of AhRAdQ mice compared with AhRfl/fl controls, regardless of treatment group (VEH groups: AhRfl/fl, 1.62 ± 0.67; AhRAdQ, 3.52 ± 0.68; p < 0.05; PCB-77 groups: AhRfl/fl, 1.29 ± 0.49; AhRAdQ, 2.12 ± 0.68 ΔΔCt; p < 0.05). In liver or soleus muscle from HF-fed mice administered VEH, there was no significant effect of genotype on AhR mRNA abundance (see Supplemental Material, Figure S2; p = 0.06). However, administration of PCB-77 resulted in a significant increase in AhR mRNA abundance in liver but not in soleus muscle from HF-fed mice of each genotype, with no significant differences between genotypes (see Supplemental Material, Figure S2; 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