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Toxicol Sci. 2013 Aug;134(2):335-44. doi: 10.1093/toxsci/kft108. Epub 2013 May 6.

Arsenic-stimulated lipolysis and adipose remodeling is mediated by G-protein-coupled receptors.

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Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15219, USA.


Arsenic in drinking water promotes a number of diseases that may stem from dysfunctional adipose lipid and glucose metabolism. Arsenic inhibits adipocyte differentiation and promotes insulin resistance; however, little is known of the impacts of and mechanisms for arsenic effects on adipose lipid storage and lipolysis. Based on our earlier studies of arsenic-signaling mechanisms for vascular remodeling and inhibition of adipogenesis, we investigated the hypothesis that arsenic acts through specific adipocyte G-protein-coupled receptors (GPCRs) to promote lipolysis and decrease lipid storage. We first demonstrated that 5-week exposure of mice to 100 μg/l of arsenic in drinking water stimulated epididymal adipocyte hypertrophy, reduced the adipose tissue expression of perilipin (PLIN1, a lipid droplet coat protein), and increased perivascular ectopic fat deposition in skeletal muscle. Incubating adipocytes, differentiated from adipose-derived human mesenchymal stem cell, with arsenic stimulated lipolysis and decreased both Nile Red positive lipid droplets and PLIN1 expression. Arsenic-stimulated lipolysis was not associated with increased cAMP levels. However, preincubation of adipocytes with the Gi inhibitor, Pertussis toxin, attenuated As(III)-stimulated lipolysis and lipid droplet loss. Antagonizing Gi-coupled endothelin-1 type A and B receptors (EDNRA/EDNRB) also attenuated arsenic effects, but antagonizing other adipose Gi-coupled receptors that regulate fat metabolism was ineffective. The endothelin receptors have different roles in arsenic responses because only EDNRA inhibition prevented arsenic-stimulated lipolysis, but antagonists to either receptor protected lipid droplets and PLIN1 expression. These data support a role for specific GPCRs in arsenic signaling for aberrant lipid storage and metabolism that may contribute to the pathogenesis of metabolic disease caused by environmental arsenic exposures.


G-protein-coupled receptor; adipocyte; adipose; arsenic; endothelin-1; lipid storage; lipolysis.

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