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.

Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics

“…In addition, the muscles of arsenic-exposed mice had decreased resistance to fatigue and decreased force recovery after a fatiguing protocol (Fig 1). We previously reported that As(III) caused mild disruption of the muscle fibers and increased ectopic perivascular lipid accumulation (28). The images and data in Fig 2 show that arsenic increased the average myofiber area, relative to unexposed control fibers.…”

Arsenic Exposure and Subclinical Endpoints of Cardiovascular Disease

“…Arsenic exposure suppressed differentiation of human mesenchymal stem cells to adipocytes, leading to decreased expression of adiponectin [106]. In addition, arsenic added to differentiated adipocytes inhibited adiponectin generation [107], although no significant effects of the arsenic exposure on circulating adiponectin in vivo was observed. However, epidemiologic studies on arsenic exposure in relation to F2-IsoPs or adiponectin are lacking.…”

Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis

“…Low to moderate levels of arsenic in drinking water (10–250 ppb) cause remodeling of liver, vascular, and metabolic tissues in mice (Straub et al, 2008; Lemaire et al, 2011; Garciafigueroa et al, 2013; Ambrosio et al, 2014). In abdominal adipose tissue, arsenic exposure changed adipocyte phenotype and lipid storage capacity while also causing redistribution of fat to perivascular regions in skeletal muscle (Garciafigueroa et al, 2013).…”

“…Five to 6 week old male wild type C57BL/6NTac (Taconic Farms, Hudson NY) mice were exposed for 2 weeks to drinking water containing 0 or 100 μg/L trivalent arsenite, as previously described (Straub et al, 2008; Garciafigueroa et al, 2013). All studies were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh.…”