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Association between arsenic suppression of adipogenesis and induction of CHOP10 via the endoplasmic reticulum stress response.

Hou Y, Xue P, Woods CG, Wang X, Fu J, Yarborough K, Qu W, Zhang Q, Andersen ME, Pi J - Environ. Health Perspect. (2012)

Bottom Line: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs.Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.

ABSTRACT

Background: There is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis.

Objective: We sought to determine the mechanisms of arsenic suppression of adipogenesis.

Methods: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).

Results: Exposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ≤ 5 μM), inorganic arsenate (≤ 20 μM), trivalent monomethylated arsenic (MMA3+, ≤ 1 μM), and trivalent dimethylated arsenic (DMA3+, ≤ 2 μM) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein β (C/EBPβ), which regulates the transcription of peroxisome proliferator-activated receptor γ and C/EBPα.

Conclusions: Low-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBPβ transcriptional activity, thus suppressing adipogenesis. Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

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Effects of arsenicals on the DMI-induced reduction of CHOP10 in the early stage of adipogenesis in 3T3-L1 preadipocytes. (A) Effects of various arsenicals on the expression of CHOP10 protein in the early stage of adipogenesis. Cells were treated 1 day after confluence with DMI in the absence (control) or presence of arsenicals. Vehicle, growth medium. (B–D) Quantification of the protein expression of CHOP10 in response to iAs3+, iAs5+, or MMA3+ exposure in the early stage of adipogenesis (n = 3). *p < 0.05, compared with control cells at the same time. #p < 0.05, compared with vehicle-treated control cells.
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f5: Effects of arsenicals on the DMI-induced reduction of CHOP10 in the early stage of adipogenesis in 3T3-L1 preadipocytes. (A) Effects of various arsenicals on the expression of CHOP10 protein in the early stage of adipogenesis. Cells were treated 1 day after confluence with DMI in the absence (control) or presence of arsenicals. Vehicle, growth medium. (B–D) Quantification of the protein expression of CHOP10 in response to iAs3+, iAs5+, or MMA3+ exposure in the early stage of adipogenesis (n = 3). *p < 0.05, compared with control cells at the same time. #p < 0.05, compared with vehicle-treated control cells.

Mentions: CHOP10 induction in adipogenic suppression by arsenic. To further elucidate the involvement of UPR and CHOP10 induction in the arsenic-induced suppression of adipogenesis, the protein expression of CHOP10 was determined during the early stage of DMI-induced adipogenesis. As shown in Figure 5, the expression of CHOP10 in untreated control cells significantly decreased along with the DMI treatment. Comparing with control cells, iAs3+ treatment caused significantly attenuated and delayed DMI-induced reduction of CHOP10 protein expression (Figure 5A,B). In agreement with the effects on adipogenesis, MMA3+ and iAs5+, but not MMA5+, also significantly blocked the DMI-induced reduction of CHOP10 protein expression (Figure 5A,B). These findings suggest that the inhibition of terminal adipogenesis by iAs3+, MMA3+, and iAs5+ is, at least in part, due to an inability to decrease CHOP10 in the initiation phase of adipogenesis. DMA3+ did not affect DMI-induced reduction of CHOP10 protein expression during the early stage of adipogenesis, suggesting DMA3+ impairs adipogenesis by a different mechanism.


Association between arsenic suppression of adipogenesis and induction of CHOP10 via the endoplasmic reticulum stress response.

Hou Y, Xue P, Woods CG, Wang X, Fu J, Yarborough K, Qu W, Zhang Q, Andersen ME, Pi J - Environ. Health Perspect. (2012)

Effects of arsenicals on the DMI-induced reduction of CHOP10 in the early stage of adipogenesis in 3T3-L1 preadipocytes. (A) Effects of various arsenicals on the expression of CHOP10 protein in the early stage of adipogenesis. Cells were treated 1 day after confluence with DMI in the absence (control) or presence of arsenicals. Vehicle, growth medium. (B–D) Quantification of the protein expression of CHOP10 in response to iAs3+, iAs5+, or MMA3+ exposure in the early stage of adipogenesis (n = 3). *p < 0.05, compared with control cells at the same time. #p < 0.05, compared with vehicle-treated control cells.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569692&req=5

f5: Effects of arsenicals on the DMI-induced reduction of CHOP10 in the early stage of adipogenesis in 3T3-L1 preadipocytes. (A) Effects of various arsenicals on the expression of CHOP10 protein in the early stage of adipogenesis. Cells were treated 1 day after confluence with DMI in the absence (control) or presence of arsenicals. Vehicle, growth medium. (B–D) Quantification of the protein expression of CHOP10 in response to iAs3+, iAs5+, or MMA3+ exposure in the early stage of adipogenesis (n = 3). *p < 0.05, compared with control cells at the same time. #p < 0.05, compared with vehicle-treated control cells.
Mentions: CHOP10 induction in adipogenic suppression by arsenic. To further elucidate the involvement of UPR and CHOP10 induction in the arsenic-induced suppression of adipogenesis, the protein expression of CHOP10 was determined during the early stage of DMI-induced adipogenesis. As shown in Figure 5, the expression of CHOP10 in untreated control cells significantly decreased along with the DMI treatment. Comparing with control cells, iAs3+ treatment caused significantly attenuated and delayed DMI-induced reduction of CHOP10 protein expression (Figure 5A,B). In agreement with the effects on adipogenesis, MMA3+ and iAs5+, but not MMA5+, also significantly blocked the DMI-induced reduction of CHOP10 protein expression (Figure 5A,B). These findings suggest that the inhibition of terminal adipogenesis by iAs3+, MMA3+, and iAs5+ is, at least in part, due to an inability to decrease CHOP10 in the initiation phase of adipogenesis. DMA3+ did not affect DMI-induced reduction of CHOP10 protein expression during the early stage of adipogenesis, suggesting DMA3+ impairs adipogenesis by a different mechanism.

Bottom Line: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs.Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.

ABSTRACT

Background: There is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis.

Objective: We sought to determine the mechanisms of arsenic suppression of adipogenesis.

Methods: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).

Results: Exposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ≤ 5 μM), inorganic arsenate (≤ 20 μM), trivalent monomethylated arsenic (MMA3+, ≤ 1 μM), and trivalent dimethylated arsenic (DMA3+, ≤ 2 μM) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein β (C/EBPβ), which regulates the transcription of peroxisome proliferator-activated receptor γ and C/EBPα.

Conclusions: Low-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBPβ transcriptional activity, thus suppressing adipogenesis. Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

Show MeSH
Related in: MedlinePlus