Association between Arsenic Suppression of Adipogenesis and Induction of CHOP10 via the Endoplasmic Reticulum Stress Response

Yongyong Hou,^1* Peng Xue,^1* Courtney G. Woods,¹ Xia Wang,^1,2 Jingqi Fu,¹ Kathy Yarborough,¹ Weidong Qu,² Qiang Zhang,¹ Melvin E. Andersen,¹ and Jingbo Pi¹


¹Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA; ²School of Public Health, Fudan University, Shanghai, China


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.


Key words: adipogenesis, arsenic, C/EBP, CHOP10, preadipocytes, type 2 diabetes. 


Environ Health Perspect 121:237–243 (2013). http://dx.doi.org/10.1289/ehp.1205731 [Online 5 December 2012]


Address correspondence to J. Pi, The Hamner Institutes for Health Sciences, 6 Davis Dr., Research Triangle Park, NC 27709, USA. Telephone: (919) 558-1395. Fax: (919) 558-1305. E-mail: jpi@thehamner.org


*These authors contributed equally to this study. 


Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205731).


The content is solely the responsibility of the authors. The Hamner Institutes for Health Sciences is a 501(c)3 not-for-profit organization that has a diverse research portfolio that includes funding from the American Chemistry Council, a trade association that represents chemical manufacturers.


This research was supported in part by National Institutes of Health grant ES016005 to J.P. M.E.A. received funding from the DOW Chemical Company and Unilever. The other authors declare they have no actual or potential competing financial interests. 


Received 8 July 2012; Accepted 4 December 2012; Online 5 December 2012.