Vitamin D Limits Chemokine Expression in Adipocytes and Macrophage Migration In Vitro and in Male Mice

Abstract

Vitamin D (VD) displays immunoregulatory effects and reduces adipocyte inflammation, which may participate to a reduction of adipose tissue macrophage infiltration in the context of obesity-associated low-grade inflammation. These observations have been described mainly in vitro, through the evaluation of a limited number of inflammatory markers. Here, we studied the effects of 1,25 dihydroxy-VD on chemokine network expression in adipocytes (by transcriptomic approach), and we confirm the physiological relevance of these data in vivo, by demonstrating the effect of VD on cytokine and chemokine gene expression as well as on macrophage infiltration in adipose tissue. 1,25 dihydroxy-VD down-regulated (-1.3- to -10.8-fold) the mRNA expression of 29 chemokines and limited macrophage migration in TNFα-conditioned adipocyte medium (1.5-fold; P < .05). This effect was associated with a reduction in p65 and IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (2-fold compared with TNFα; P < .05). The effects of VD were confirmed in mice injected ip with lipopolysaccharide (acute inflammation) and diet-induced obese mice (metabolic inflammation), where the levels of mRNA encoding proinflammatory cytokines and chemokines (∼2-fold) were reduced in adipocytes (acute and metabolic inflammation) and adipose tissue and that macrophage infiltration was also inhibited in the adipose tissue of obese mice (metabolic inflammation). Altogether, these results showed that VD displayed a global immunoregulatory impact on adipocytes, notably via the inhibition of chemokine expression and macrophage infiltration in inflamed adipose tissue.

Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link?

“…AT represents not only the main site of vitamin D accumulation in humans, but also a main target of vitamin D action. AT-vitamin D hydroxylases are capable of locally converting this hormone in its active forms [25,26] which display autocrine and paracrine immunoregulatory actions through the specific vitamin D receptor [27,28]. It is plausible, indeed, that chronic DPP4 inhibition modulates AT inflammation and stimulates vitamin D activation/mobilization from adipocytes into the bloodstream.…”

Genetic Factors and Molecular Mechanisms of Vitamin D and Obesity Relationship

“…Besides the observed effects, vitD decreases proinflammatory cytokines and chemokines in mice after an injection of lipopolysaccharide and in diet-induced obese mice, which caused a metabolic inflammation [61]. In humans, a negative association was found between serum 25(OH)-D concentration and plasma interleukin (IL)-6 and TNF-α levels in normal-weight subjects.…”

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

“…Interestingly, Zoico et al recently demonstrated that VD, similarly to 1,25(OH) 2 D, was able to blunt the lipopolysaccharide-mediated pro-inflammatory effect in human adipocytes (37) . Using a microarray approach, we recently demonstrated that 1,25(OH) 2 D was able to downregulate a large set of chemokines (80) induced by inflammatory stimulus (81) in human and murine adipocytes. This effect was accompanied by a reduction of macrophage migration mediated by an adipocyte-conditioned medium (80) .…”

“…Using a microarray approach, we recently demonstrated that 1,25(OH) 2 D was able to downregulate a large set of chemokines (80) induced by inflammatory stimulus (81) in human and murine adipocytes. This effect was accompanied by a reduction of macrophage migration mediated by an adipocyte-conditioned medium (80) . These anti-inflammatory properties of 1,25(OH) 2 D have also been established in several types of immune cells found in the adipose tissue, including lymphocytes and macrophages (78) .…”