ROLE OF ARGINASE IN OBESITY-INDUCED VISCERAL ADIPOSE TISSUE DYSREGULATION AND ENDOTHELIAL DYSFUNCTION

Abstract

An obesity epidemic continues to rise worldwide. Visceral (central) obesity is an important concern as it correlates with metabolic and cardiovascular pathologies. Arginase is a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial). We found that visceral adipose tissue (VAT) from obese WT mice fed a high fat/high sucrose diet (HFHS) showed a significantly higher expression of A2 compared to mice fed normal chow diet (ND). We also observed that A2 expression is upregulated 3-fold in differentiated 3T3- L1 adipocytes exposed to high levels of palmitate and glucose, a mimic of the obese state, compared to control media. Our study focused on the involvement of A2 in obesity associated metabolic and vascular disorders. WT mice and those globally lacking A2 (A2-/-) were fed HFHS or ND for 16 weeks. The HFHS diet-induced increases in body and VAT weights and total adiposity were prevented or reduced in A2-/- mice. In concert, metabolic chamber studies revealed that energy expenditure and fatty acid oxidation rates were significantly higher in A2-/- compared to WT HFHS mice. VAT from A2-/- mice fed HFHS had higher levels of active AMPK-α, the master regulator of fatty acid metabolism, as well as higher adipocyte expression of genes involved in fatty acid β-oxidation and oxidative phosphorylation, along with preserved mitochondrial density compared to WT HFHS. A2 deletion also prevented HFHS-induced fibrous tissue deposition and inflammation in VAT, which contributed to adipocyte metabolic dysfunction. These results indicate that A2 is involved in metabolic dysfunctions. To gain insights into the role of A2 in adipocytes, primary preadipocytes isolated from VAT of A2-/- mice and differentiated in vitro showed increased expression of adiponectin and better mitochondrial function. Adenoviral overexpression of A2 in differentiated 3T3-L1 cells showed impaired mitochondrial function and increased mitochondrial ROS. Obesity-related metabolic disorders increase the risk of cardiovascular diseases, the leading global cause of death. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2-/- mice, but more prominently prevented in A1+/- mice. In conclusion, A2 is critically involved in HFHS-induced obesity, VAT inflammation and metabolic dysregulation. Both A1 and A2 are involved in HFHS-induced vascular endothelial dysfunction.