title: Arsenic-stimulated lipolysis and adipose remodeling is mediated by G-protein-coupled receptors.
abstract: 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.
authors: Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15219, USA.
authors: D Yesica
authors: DY
authors: Garciafigueroa
authors: Linda R
authors: LR
authors: Klei
authors: Fabrisia
authors: F
authors: Ambrosio
authors: Aaron
authors: A
authors: Barchowsky
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D005260:Female; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044022:Receptor, Endothelin A / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D044022:Receptor, Endothelin A; D043562:Receptors, G-Protein-Coupled; D001151:Arsenic
keywords: G-protein-coupled receptor; adipocyte; adipose; arsenic; endothelin-1; lipid storage; lipolysis.
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