Dietary calcium regulates ROS production in aP2-agouti transgenic mice on high-fat/high-sucrose diets

Abstract

Objective: We have previously demonstrated that 1a, 25(OH) 2 D 3 promotes adipocyte reactive oxygen species (ROS) production. We have now evaluated whether decreasing 1a, 25(OH) 2 D 3 levels by increasing dietary calcium will decrease oxidative stress in vivo. Methods: We fed low-calcium (0.4% Ca) and high-calcium (1.2% Ca from CaCO 3 ) obesity-promoting (high sucrose/high fat) diets to aP2-agouti transgenic mice and assessed regulation of ROS production in adipose tissue and skeletal muscle. Results: Mice on the high-calcium diet gained 50% of the body weight (P ¼ 0.04) and fat (Po0.001) as mice on the low-calcium diet (0.4% Ca). The high-calcium diet significantly reduced adipose intracellular ROS production by 64 and 18% (Po0.001) and inhibited adipose tissue nicotinamide adenine dinucleotide phosphate oxidase expression by 49% (P ¼ 0.012) and 63% (P ¼ 0.05) in visceral and subcutaneous adipose tissue, respectively. Adipocyte intracellular calcium ([Ca 2 þ ]i) levels were suppressed in mice on the high-calcium diet by 73-80% (Po0.001). The high-calcium diet also induced 367 and 191% increases in adipose mitochondrial uncoupling protein 2 (UCP2) expression (Po0.001) in visceral and subcutaneous adipose tissue, respectively. The pattern of UCP3 expression and indices of ROS production in skeletal muscle were consistent with those in adipose tissue. The high-calcium diet also suppressed 11b-hydroxysteroid dehydrogenase (11b-HSD) expression in visceral adipose tissue by 39% (P ¼ 0.034). 11b-HSD expression was markedly higher in visceral vs subcutaneous adipose tissue in mice on the low-calcium diet (P ¼ 0.034), whereas no difference was observed between the fat depots in mice on the high-calcium diet. Conclusion: These data support a potential role for dietary calcium in the regulation of obesity-induced oxidative stress.

Role of Calcitriol and Cortisol on Human Adipocyte Proliferation and Oxidative and Inflammatory Stress: A Microarray Study

“…Consistent with these observations, data from the present study indicate that calcitriol may increase multiple inflammatory cytokine and decreased anti-inflammatory cytokine transcription. In addition, data from the present study suggest that calcitriol also favors cytoplasmic oxidative stress by increasing NADPH oxidase expression, and our previous data demonstrate a regulatory effect of calcitriol on NAPDH oxidase expression [9] . However, this effect was absent with the combination of calcitriol with cortisone; attenuation of this effect by cortisone may contribute to the anti-inflammatory function of glucocorticoid.…”

“…Although the mechanism responsible for the development of systemic inflammation is not clear, multiple previous studies indicated that increased oxidative stress in accumulated fat is an underlying cause of dysregulation of adipocytokines [34][35][36][37] . We have shown previously that calcitriol was associated with oxidative stress and inflammation and stimulated the expression of multiple inflammatory cytokines in human adipocytes, while suppression of calcitriol by dietary calcium suppressed ROS and inflammatory cytokines independent of its anti-obesity effects [9] . Consistent with these observations, data from the present study indicate that calcitriol may increase multiple inflammatory cytokine and decreased anti-inflammatory cytokine transcription.…”

“…In addition, we also demonstrate that physiological doses of calcitriol inhibit apoptosis in differentiated human and 3T3-L1 adipocytes [14] , and that the suppression of calcitriol in vivo by increasing dietary calcium stimulates adipocyte apoptosis in aP2 transgenic mice [14] , suggesting that the stimulation of adipocyte apoptosis contributes to the observed reduction in adipose tissue mass after administration of high calcium diets. Moreover, we also recently demonstrated that calcitriol increases oxidative stress by inhibiting UCP2 expression [9] and increasing [Ca 2+ ] i , and consequently favors adipocyte proliferation [20] . Accordingly, the suppression of calcitriol by increasing dietary calcium attenuates adipocyte triglyceride accumulation and causes a net reduction in fat mass in both mice and humans in the absence of caloric restriction [21] , a marked augmentation of body weight and fat loss during energy restriction in both mice and humans [21][22][23] , and a reduction in the rate of weight and fat regain following energy restriction in mice [19] .…”

“…If Excess fat mass may result, in part, from recruitment of new adipocytes, and the adipogenic potential of precursor cells may be an important determinant in fat mass regulation and obesity-associated disorders [27,28] . We have previously shown that calcitriol stimulates adipocyte proliferation and this effect was associated with a stimulation of oxidative stress [9,20] . Indeed, suppression of calcitriol by increasing dietary calcium suppressed fat mass accumulation in humans and in a rodent model of obesity [8] .…”

“…Local adipose tissue glucocorticoid levels and intracellular glucocorticoid availability are controlled by the activity of 11 ␤ -hydroxysteroid dehydrogenase type 1 (11 ␤ -HSD-1) to generate active cortisol from inactive cortisone [6,7] . Previous studies from this laboratory demonstrate an anti-obesity effect of dietary calcium [8] , and that this effect is associated with preferential loss of central adipose tissue [9,10] . Increasing dietary calcium inhibits lipogenesis [11] , stimulates energy metabolism [12,13] and increases adipocyte apoptosis [14] .…”