Exercise Training in the Metabolic Syndrome Improves Perivascular Adipose Gene Expression
Authors: DeVallance Evan , Branyan Kayla , Lemaster Kent , Skinner Roy , Brooks Steve , Sheets Whitney , Bryner Randall , Frisbee Jefferson , Chantler Paul 
Published: November 2023

Metabolic syndrome (MetS) is a major risk factor of cardiovascular disease and exercise is recognized for preventing and reversing cardiovascular impairments. Evidence suggests perivascular adipose tissue (PVAT) plays an active roll in vascular function and structure. PVAT is known to release vasoactive substances such as nitric oxide (NO), which may contribute directly to vascular tone. In disease states PVAT may undergo whitening, shifting its phenotype from brown to white reflected by decreased expression of uncoupling protein‐1 (UCP1). Obesity is associated with this whitening of PVAT and a loss of beneficial actions. Further inflammatory markers (IL‐6, and TNF α) along with reactive oxygen species (ROS) released from PVAT may effect aortic endothelium's production of NO. These same cytokines may affect the expression of extracellular matrix remodeling proteins (MMP 2 and 9, and their inhibitors TIMPs), which may alter aortic stiffness. The purpose of the current study is to determine how the presence of MetS alters PVAT phenotype (UCP1), NO and matrix remodeling expression, and to what extent exercise training can affect PVAT expression of above substances.

Aortic PVAT was obtained from obese Zucker rats (OZR) a model of MetS, and their lean counterparts (LZR), who either remained inactive or underwent treadmill running for 8 weeks. Using qPCR, PVAT mRNA expression was examined. OZR had a whitening of PVAT shown by a 103‐fold decrease in UCP1. This whitening of PVAT leading to a robust increase in inflammatory cytokine expression (IL‐6 390,000 fold and TNF α 74 fold), with a minor decrease in SOD1 (1.3fold). Such changes may leave the PVAT ill equipped to deal with the increase of ROS associated with MetS. These changes are accompanied by MetS up‐regulation of eNOS (1.8 fold increase, p≤ 0.001) and a decrease in Gch1 (1.6 fold, p≤ 0.001) expression in OZR, suggesting coupling of eNOS may be disrupted. The increase in inflammation and decrease in antioxidant system may also promote increases in remodeling factors. Indeed, MetS caused an increase in both MMP2 (2.3 fold) and MMP9 (6.6 fold) expression, accompanied by a decrease (1.6 fold) in the expression of the inhibitor TIMP1. Foremost exercising led to re‐browning of PVAT with UCP1 up‐regulated 29 fold in OZR. This was followed by improved PVAT SOD1 (3.2 fold p≤ 0.05) expression and a decreased production of IL‐6 (22 fold p≤ 0.05) and TNF α (2.1 fold). Improving the local aortic environment with decreased ROS and inflammation with exercise appeared to balance expression of eNOS (1.2 fold decrease) and Gch1 (2.3 fold increase) suggesting better eNOS coupling and function. Exercise also reduced MMP‐2 (1.3 fold) and MMP9 (8 fold), possible showing beneficial effects of exercise lowering elastase production in PVAT. In conclusion, MetS causes a whitening of PVAT, increased inflammation, decrease in SOD1. These changes may alter the PVAT environment promoting arterial remodeling and increased vascular tone. Exercise combated these MetS impairments by a re‐browning of the PVAT, improving the antioxidant system, reducing inflammation, improving the BH4 pathway, and decreasing MMPs.

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