Abstract
Body fat distribution contributes to obesity-related metabolic and cardiovascular disorders. Visceral fat is more detrimental than subcutaneous fat. However, the mechanisms underlying visceral fat-mediated cardiometabolic dysregulation are not completely understood. Localized increases in expression of the renin angiotensin system (RAS) in adipose tissue (AT) may be implicated. We therefore investigated mRNA and protein expression of RAS components in visceral versus subcutaneous AT using paired samples from individuals undergoing surgery (N = 20, body mass index: 45.6 ± 6.2 kg/m2, and age: 44.6 ± 9.1 years). We also examined RAS-related proteins in AT obtained from individuals on renin angiotensin aldosterone system (RAAS) targeted drugs (N = 10, body mass index: 47.2 ± 9.3 kg/m2, and age: 53.3 ± 10.1 years). Comparison of protein expression between subcutaneous and visceral AT samples showed an increase in renin (p = 0.004) and no change in angiotensinogen (p = 0.987) expression in visceral AT. Among proteins involved in angiotensin peptide generation, angiotensin converting enzyme (p = 0.02) was increased in subcutaneous AT while chymase (p = 0.001) and angiotensin converting enzyme-2 (p = 0.001) were elevated in visceral fat. Furthermore, visceral fat expression of angiotensin II type-2 receptor (p = 0.007) and angiotensin II type-1 receptor (p = 0.031) was higher, and MAS receptor (p < 0.001) was lower. Phosphorylated-p53 (p = 0.147), AT fibrosis (p = 0.138) and average adipocyte size (p = 0.846) were similar in the two depots. Nonetheless, visceral AT showed increased mRNA expression of inflammatory (TNFα, p < 0.001; IL-6, p = 0.001) and oxidative stress markers (NOX2, p = 0.038; NOX4, p < 0.001). Of note, mRNA and protein expression of RAS components did not differ between subjects taking or not taking RAAS related drugs. In summary, several RAS related proteins are differentially expressed in subcutaneous versus visceral AT. This differential expression may not alter AngII but likely increases Ang1-7 generation in visceral fat. These potential differences in active angiotensin peptides and receptor expression in the two depots suggest that localized RAS may not be involved in differences in visceral vs subcutaneous AT function in obese individuals. Our findings do not support a role for localized RAS differences in visceral fat-mediated development of cardiovascular and metabolic pathology.
Highlights
Obesity results in heightened vulnerability to cardiovascular and metabolic disorders (Saydah et al, 2014)
We showed that AGT expression was not different between the two depots while renin expression was increased in visceral fat (Figure 1)
The mRNA and protein expression of AGT and renin did not vary with use of renin angiotensin aldosterone system (RAAS) targeted drug and there were no interactions between drug use and depots
Summary
Obesity results in heightened vulnerability to cardiovascular and metabolic disorders (Saydah et al, 2014). RAS constitutes a complex cascade of pathways through which AGT is converted to form bioactive peptides, AngII and angiotensin 1–7 (Ang1-7), via multistep-enzymatic processes including renin, ACE, chymase, and ACE homolog-2 (ACE2) (Chappell, 2016). These peptides mediate their cellular effects through AngII type-1 receptor (AT1R), AngII type-2 receptor (AT2R), and MASR. AngII activates p53 pathway to mediate its downstream cellular effects (Grishko et al, 2003; Liu et al, 2009; Guan et al, 2013). P53 has been shown to play an important role in oxidative stress, insulin signaling, angiogenesis, apoptosis, inflammation, and fibrosis in different cells including AT (Minamino et al, 2009; Shimizu et al, 2012; Ghosh et al, 2013; Gogiraju et al, 2015)
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