Imbalanced Periaortic Adipose Tissue Brown‐to‐Inflammatory Phenotype is Related to Aortic Stiffness

Abstract

Obesity‐mediated periaortic adipose tissue (AT) inflammation has been implicated in aortic stiffness, which is an established independent predictor for cardiovascular disease and mortality. However, whether increased browning of periaortic AT confers vascular protection in the setting of obesity remains unknown. Herein, we hypothesized that enhanced periaortic AT browning via interscapular brown AT lipectomy (iBATx) would mitigate obesity‐induced aortic stiffness. Accordingly, four groups of male mice (C57BL/6J) fed normal chow (NC) or Western diet (WD) for 18 weeks following sham or iBATx surgery were studied. NC‐fed leptin receptor deficient (db−/db−) adult male mice were also studied as another model of diet‐induced obesity. Aortic stiffness was assessed via pulse wave velocity and periaortic AT phenotype was determined via gene expression. Counter to our hypothesis, in the absence of periaortic AT inflammation, increased expression of browning genes in iBATx mice was associated with increased aortic stiffness (1.5‐fold vs. sham, P<0.05). This association was abrogated when increased expression of browning genes co‐existed with increased expression of inflammatory genes (i.e., WD‐fed sham and iBATx mice). Reciprocally, low expression of browning genes in db−/db− mice was also associated with increased aortic stiffness, relative to wild‐type controls (1.6‐fold, P<0.05). Importantly, when computing the ratio of browning‐to‐inflammatory gene expression (B/I ratio) across groups using a composite score (average of fold‐differences) of classical browning genes (UCP1, PGC1α, PRDM16, Cidea, FGF‐21) vs. inflammatory genes (IL‐1β, TNFα, MCP‐1, CD68), we found a U‐shaped polynomial relationship between the periaortic AT B/I ratio and aortic stiffness with an R2 of 0.97. That is, increased and decreased periaortic AT B/I ratios were associated with increased aortic stiffness. Of note, this polynomial relationship between AT B/I ratio and aortic stiffness was less apparent in visceral white (i.e., epididymal) AT (R2=0.36), supporting the notion that the phenotype of periaortic AT is particularly related to aortic stiffness, compared to other distant AT depots. In conclusion, these findings set forth the new hypothesis that an imbalanced periaortic AT browning‐to‐inflammatory phenotype may be an important determinant of aortic stiffness in mice.