PMID:23152186

Citation	Klei, LR, Garciafigueroa, DY and Barchowsky, A' (2012) Arsenic activates endothelin-1 Gi protein-coupled receptor signaling to inhibit stem cell differentiation in adipogenesis. Toxicol. Sci. '
Abstract	Dysfunctional lipid and glucose metabolism contribute to metabolic syndrome; a major public health concern that enhances cardiovascular disease risk. Arsenic (As(III)) exposure may increase metabolic syndrome and cardiovascular disease risk by impairing adipose tissue differentiation, function, and insulin sensitivity through pathogenic mechanisms that remain unclear. We hypothesized that As(III) signals through the Pertussis toxin (Ptx) sensitive, Gi protein-coupled (GPCR) to impair adipogenesis, as previously demonstrated for its stimulation of vascular oxidant generation, angiogenesis, and remodeling. Since both As(III) and GPCR ligands inhibit progenitor cell differentiation into adipocytes, we investigated the hypothesis in an model of low passage human mesenchymal stem cells (hMSC). As(III) (0.1-1.0 μM) suppressed dexamethasone/insulin-induced hMSC adipogenesis, as indicated by: decreased transcriptional promoters of differentiation; decreased fat droplet formation; and decreased expression of differentiated adipocyte markers, such as adiponectin (ADIPOQ) and perilipin (PLIN1). Pre-incubating hMSC with Ptx prevented 90% of the suppressive effect of As(III). Selective competitive antagonists of Gi-coupled endothelin-1 type A and B receptors were approximately 60% effective in blocking As(III) inhibition and combination of antagonists to both receptors were 85% effective. In contrast, antagonists to the sphingosine-1-phosphate type 1 receptor (previously shown to mediate As(III) vascular effects) or the angiotensin II type 1 receptor were ineffective in blocking As(III) effects. These studies suggest a majority of arsenic-inhibited adipocyte differentiation and metabolism requires endothelin-1 GPCRs and that As(III) effects on GPCR signaling are tissue and context specific. This may represent a significant mechanism for the contribution of arsenic exposure to increased metabolic and cardiovascular diseases.
Links	PubMed Online version:10.1093/toxsci/kfs323
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:AS3MT		GO:0050922: negative regulation of chemotaxis	ECO:0000314:		P		Fig 2. As(III) causes concentration dependent inhibition of hMSC differentiation to adipocytes.	complete CACAO 6133
MOUSE:AS3MT		GO:0045444: fat cell differentiation	ECO:0000315:		P		Fig 3. As(III) must be present early to inhibit adipocyte differentiation.	complete CACAO 6134

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