Role of Arginase 2 in Systemic Metabolic Activity and Adipose Tissue Fatty Acid Metabolism in Diet-Induced Obese Mice.

Reem Atawia,Christopher Cutler,Nicole Yiew,Neal Weintraub,Haroldo Toque,Mohamed Meghil,Robert Caldwell,Ruth Caldwell,Tyler Benson

doi:10.3390/ijms20061462

Abstract

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction.

Highlights

Obesity, central obesity, is associated with chronic inflammation and is considered to be a key contributor to metabolic dysfunctions
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Our study found that A2 deletion ameliorated the diet-induced increase in body weight, whole-body adiposity, visceral adipose tissue (VAT) weight, adipocyte hypertrophy, and insulin resistance

Summary

Introduction

Central obesity, is associated with chronic inflammation and is considered to be a key contributor to metabolic dysfunctions It is an independent risk factor for all-cause mortality, and is an especially high-risk factor for cardiovascular diseases [1,2,3,4]. During obesity, adipocytes have an altered adipokine secretion profile in which pro-inflammatory adipokines are elevated and anti-inflammatory adipokines, such as adiponectin, are reduced further exacerbating this deleterious environment. These compounding effects lead to chronic inflammation, insulin resistance, and development of cardiovascular disease [9]. This can be achieved by activating 5 adenosine monophosphate-activated protein kinase-α (AMPK-α), the central regulator of energy homeostasis that promotes energy conservation and induces fatty acid β-oxidation [11]

Methods

Results

Conclusion