Dietary calcium and calcitriol regulation of the adipose tissue renin‐angiontensin system (RAS) and inflammatory cytokine production

Abstract

Antagonism of the RAS may reduce type-2 diabetes risk, as angiotensin II modulates diabetogenic factors such as inflammatory cytokines and oxidative stress. Moreover, the local RAS modulates adipocyte function. Our previous data demonstrate that diet-induced obesity results in increased local oxidative stress and inflammatory cytokine production in adipose tissue, and that increasing dietary calcium attenuates this effect via regulation of calcitriol production. Accordingly, we investigated the effect of dietary calcium in regulation of the adipose tissue RAS in aP2-agouti transgenic mice and the role of RAS in modulating calcitriol regulation of inflammatory cytokine production in 3T3-L1 adipocytes. Dietary calcium significantly suppressed expression of angiotensinogen (80%, p<0.001), angiotensin II receptor type I (62%, p<0.001) and ACE (71%, p<0.001) in mouse visceral fat, suggesting that dietary calcium inhibits local RAS activity; RAS components were expressed at a lower level in subcutaneous adipose tissue, and each was comparably suppressed by dietary calcium (p=0.004). Moreover, calcitriol and angiotensin II each stimulated TNF α and IL-6 expression by ~2-fold in 3T3-L1 adipocytes (p<0.005), and the effect of calcitriol was attenuated by ACE inhibition with enalapril. Thus, the local RAS has a direct role in regulating inflammatory cytokine production in adipocytes, and calcitriol further promotes inflammatory cytokine production via a RAS-dependent mechanism. Collectively, these data suggest that dietary calcium regulates the local RAS in adipose tissue thereby inhibits inflammatory cytokine production.