Obesity‐induced metabolic and vascular dysregulation: Implication of arginase

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Obesity epidemic continues to rise worldwide, currently affecting more than 2 billion people. Visceral (central) obesity is of great importance as it correlates with metabolic and cardiovascular pathologies associated with chronic inflammation. Arginase, a ureahydrolase enzyme with two isoforms (A1‐cytosolic and A2‐mitochondrial). A2 expression is upregulated 3‐fold in differentiated adipocytes (3T3‐L1) exposed to high levels of palmitate (250 μM) and glucose (25 mM), a mimic of the obese state, as compared to adipocytes in control media. Also, visceral adipose tissue (VAT) from obese WT male and female mice showed a significantly higher expression of A2 compared to lean mice (p<0.05). Our study aimed to examine the involvement of A2 in obesity‐associated metabolic and vascular disorders. Male and female WT mice and those globally lacking A2 (−/−) were fed either high fat, high sucrose (HFHS) or normal diet (ND) for 16 weeks. Body weight was measured weekly and metabolic parameters were determined by indirect calorimetry. The HFHS diet‐induced increases in body and VAT weights, as well as total body adiposity, were prevented or reduced in A2−/− mice. In concert, A2−/− HFHS mice exhibited 30% reduction in blood glucose and increased energy expenditure by 20% in males and 40% in females compared to WT HFHS mice (p<0.05). WT and A2−/− mice fed HFHS showed a significantly reduced respiratory exchange ratio compared to ND mice. However, there was no significant difference in food consumption or locomotor activity. One strategy to combat obesity is to induce energy expenditure in white adipose tissue through elevated fatty acid oxidation. Mature adipocytes isolated using collagenase digestion from VAT of WT HFHS male mice showed significantly reduced expression of PGC‐1α, PPAR‐Ɣ and adiponectin compared to WT ND (p<0.05). A2 deletion markedly blunted their reduction with a concomitant increase of VAT p‐AMPK‐α and adipocyte expression of genes involved in fatty acid metabolism. It also prevented the HFHS‐induced loss of mitochondrial density. Inflammation and fibrosis are involved in VAT metabolic dysfunctions. Flow cytometry revealed a 2‐fold increased infiltration of inflammatory M1‐like macrophages in VAT stromal vascular fraction from WT HFHS vs ND mice. VAT fibrosis was significantly greater in WT HFHS vs ND mice. These effects were prevented in A2−/− HFHS mice. Studies using primary preadipocytes isolated from VAT of male A2−/− mice showed increased expression of adiponectin and p‐AKT following insulin treatment vs WT mice, which indicates higher insulin sensitivity. Aortic rings from WT HFHS mice showed impaired endothelium‐dependent vasorelaxant responses to acetylcholine vs ND mice. Vasorelaxant responses were maintained in A2−/− HFHS and even more prominently in A1+/− HFHS mice. In conclusion, A2 is critically involved in HFHS‐induced VAT inflammation and metabolic dysregulation.Support or Funding InformationR01 HL070215, R01 EY01176 & AHA17PRE33660321This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.