Receptor cross talk in arsenic-impaired fat metabolism

Metabolic syndrome is a major public health concern that increases cardiovascular risk from dysfunctional lipid and glucose metabolism. Many factors, including genetics and environmental factors, such as inorganic arsenic, contribute to increase the risk for the disease. However, the mechanisms for this correlation are not well understood. This study tested the main hypothesis that arsenic alters proper lipid storage, remodeling and metabolic changes in adipose tissue through specific activation of membrane receptors in adipocytes. Mice exposed to arsenic through drinking water demonstrated that circulating levels of insulin and tryacylglycerides were affected. Moreover, arsenic stimulated adipose tissue remodeling and angiogenesis in epididymal fat pads, as well as redistribution of fat in ectopic tissues.\ud In a model of cultured adipocytes, arsenic induced loss of lipid droplets and expression of lipid-coated protein perilipin (PLIN-1).Lipolytic activity was also stimulated by arsenic within 24 hour of exposure and sustained after 3 days, which was indicative of aberrant lipid storage. The prevention of arsenic effects through pertussis toxin sensitive pathways strongly suggested that a Gi –linked receptors mediates arsenic toxicity. Further investigation revealed that the G-protein coupled receptors (GPCR) endothelin-1 receptor A (EDNRA) and B (EDNRB) were activated by arsenic. The selective blocking of EDNRA with BQ610, but not EDNRB with BQ788, partially prevented the loss of fat droplets. In contrast, both, blocking EDNRA and EDNRB prevented the increase in glycerol release by arsenic. Activation of the receptor tyrosine kinase (RTK) EGFR in response to arsenic was not mediated by Src family or oxidant stress. However, arsenic exposure induced a transient association of Gαi protein- EGFR. These results indicated a novel mechanism through which arsenic stimulates cross talk between EDNRA-EGFR.\ud In conclusion, these studies demonstrated that arsenic impairs proper functionality and metabolism of adipose tissue by stimulation of GPCR-RTK cross communication. The result of this dissertation contributes to better understand the etiology and pathophysiology of metabolic diseases. The advanced understanding of the role of environmental exposure in the etiology of diseases, such as diabetes mellitus, atherosclerosis and hypertension, seen the large population exposed to arsenic will aid in developing strategies to greatly reduce the burden of disease.\u