The Interplay Between Adipose Tissue and Vasculature: Role of Oxidative Stress in Obesity

Abstract

Cardiovascular diseases (CVDs) rank the leading cause of morbidity and mortality globally. Obesity and its related metabolic syndrome are well-established risk factors for CVDs. Therefore, understanding the pathophysiological role of adipose tissues is of great importance in maintaining cardiovascular health. Oxidative stress, characterized by excessive formation of reactive oxygen species, is a common cellular stress shared by obesity and CVDs. While plenty of literatures have illustrated the vascular oxidative stress, very few have discussed the impact of oxidative stress in adipose tissues. Adipose tissues can communicate with vascular systems, in an endocrine and paracrine manner, through secreting several adipocytokines, which is largely dysregulated in obesity. The aim of this review is to summarize current understanding of the relationship between oxidative stress in obesity and vascular endothelial dysfunction. In this review, we briefly describe the possible causes of oxidative stress in obesity, and the impact of obesity-induced oxidative stress on adipose tissue function. We also summarize the crosstalk between adipose tissue and vasculature mediated by adipocytokines in vascular oxidative stress. In addition, we highlight the potential target mediating adipose tissue oxidative stress.

Keywords: adipokines; antioxidant; perivascular adipose tissue; reactive oxygen species; vascular dysfunction.

Figure 1

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the antioxidant defense. Obesity leads to the increased systemic oxidative stress. In adipose tissue, ROS can be generated by NADPH oxidase, xanthine oxidase, and mitochondrial oxidative phosphorylation system. On one hand, the production of ROS in adipose tissue of obese subjects leads to insulin resistance, dysregulated adipokines secretion, inflammation and increased protein carbonylation. On the other hand, ROS in adipose tissue could promote adipocyte differentiation and thermogenesis in brown adipose tissue (BAT). A variety of enzymes, including superoxide dismutase (SOD), catalase, glutathione peroxidases (GPx), heme oxygenase (HO), and peroxiredoxins (Prxs), can reduce ROS burden and act as antioxidant defense in adipose tissue. Adipose tissue exerts direct effects on vascular system through releasing a wide range of bioactive products, which include circulating adipokines. Perivascular adipose tissue (PVAT) is important adipose tissue that regulates vascular function and remodeling due to its close proximity. In PVAT, the modulation of vascular contractility is conducted through the secretion of PVAT-derived relaxing factors (PVRFs) and PVAT-derived contracting factors (PVCFs). In obesity, increased oxidative stress, inflammation and eNOS dysfunction in PVAT may alter the balance between PVRFs and PVCFs. Obesity-induced PVAT dysfunction leads to the reduction of PVRFs and the production of PVCFs, hence causing enhanced vasocontraction. In addition, chronic changes in the adipokines profile may result in the pathological vascular remodeling which can further increase the risk of CVDs.

Figure 2

Functions of the antioxidant enzyme systems in adipose tissues. In adipocytes, catalase inhibits lipogenesis and Nox4 expression, which prevents weight gain and fat mass increase induced by high-fat diet. Overexpression of catalase and superoxide dismutase (SOD)-1 in adipocytes can inhibit ectopic fat accumulation and improve insulin sensitivity. Heme oxygenase 1 (HO1) can stimulate the expression of adiponectin, therefore preventing hyperglycemia and insulinemia in female mice, and improving vascular function and insulin sensitivity. Peroxiredoxin (Prx)-2 can promote adipogenesis, whereas Prx3 can stimulate the expression of adiponectin. Depletion of these antioxidant enzymes in adipocytes has shown detrimental effects in adipocyte functions and promoted cardiometabolic diseases. Glutamate-cysteine ligase (Gclc) facilitates glutathione synthesis and inhibits ROS production, thereby inhibiting ectopic fat accumulation and insulin resistance. On the other hand, deletion of either SOD2 or glutathione peroxidases (GPx) has been reported to provide beneficial effect in adipose tissue function. The anti-obesity effect of SOD2 deletion in adipocytes can be attributed to an activated mitochondrial biogenesis and enhanced mitochondrial fatty acid oxidation, which can promote energy expenditure. Insulin signaling can be enhanced by knocking down GPx in either muscle cells and hepatocytes. GPx-1 deletion can attenuate inflammation and enhance browning in visceral adipose tissues.