Journal of Obesity and Metabolic Research

: 2015  |  Volume : 2  |  Issue : 3  |  Page : 161--166

The role of Vitamin D in obesity and inflammation at adipose tissue

Wysllenny Nascimento de Souza, Ligia Araujo Martini 
 Department of Nutrition, School of Public Health, University of São Paulo, Brazil Ave. Dr. Arnaldo, 715. Zip code: 01246 904, São Paulo, Brazil

Correspondence Address:
Wysllenny Nascimento de Souza
Ave. Prof Mello de Moraes, 1235, BL G Apto 409. Zip Code: 05508 030, São Paulo


The prevalence of obesity and vitamin D deficiency has increased in the last decade, becoming pandemics. In obesity, macrophage accumulation occurs in the adipose tissue. This is associated with a low-grade chronic inflammation and leads to the release of inflammatory cytokines. Vitamin D was found to have anti-adipogenic activity and may exert immunoregulatory effects as well as reduce the adipose tissue inflammation. Recent studies suggest that vitamin D and vitamin D receptor (VDR) play an important role in adipose tissue whereas the expression of genes of the 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) and VDR were demonstrated in human adipocytes. Growing evidence suggests vitamin D also plays a role in the type of preadipocytes, and the proneness to the inflammatory process.

How to cite this article:
de Souza WN, Martini LA. The role of Vitamin D in obesity and inflammation at adipose tissue.J Obes Metab Res 2015;2:161-166

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de Souza WN, Martini LA. The role of Vitamin D in obesity and inflammation at adipose tissue. J Obes Metab Res [serial online] 2015 [cited 2020 Jul 13 ];2:161-166
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Studies suggest that the key compounds of vitamin D metabolism such as 1,25 dihydroxyvitamin (OH) D, 25 (OH) D and 1α-hydroxylase (CYP27B1) are evident in adipose tissue, indicating that vitamin D could be involved in the function of this tissue. [1],[2] In addition, adipose cells and their precursors express vitamin D receptor (VDR) and respond to 1,25 (OH) D action. [3] Adipocytes can be involved in the local synthesis as well as degradation of the biologically active form of vitamin D, given the expression of the CYP27B1 gene. The latter encodes the enzyme converting 25 (OH) D to 1,25 (OH) D and has been found in both human adipocytes and preadipocytes. [4],[5] Similarly, the CYP24 gene, which encodes the enzyme catalyzing 1,25 (OH) D , was also found to be expressed by human adipocytes and preadipocytes. [1],[4],[5] A dynamic alteration may occurs in adipose tissue during weight loss and obesity. Recently, a study has shown a low expression of CYP27B1 gene in subcutaneous adipose tissue of obese individuals. [6] This finding corroborates the ability of adipose tissue to metabolize vitamin D locally.

In fact, it has been demonstrated that bioactivation of 25 (OH) D to 1,25 (OH) D occurs in human mammary adipocytes, as well as the release of 1,25 (OH) D. [5] This discovery suggests that mature adipocytes are able to take up 25 (OH) D, and convert it to 1,25 (OH) D, and then release the biologically active compound into the adjacent microenvironment and ultimately into the circulating pool. [3] Furthermore, the VDR gene can also be active in adipose tissue, studies have shown that the VDR gene is expressed in both human adipose tissue [7] and human fat cells in culture (preadipocytes and differentiated adipocytes). [4] In summary, all evidence suggests that 25 (OH) D, 1,25 (OH) D, and VDR are involved in the adipose tissue, through the endocrine system as well as autocrine/paracrine actions of vitamin D. [1],[2],[3],[4],[5]

It is well-known that the expansion of adipose tissue occurring in obesity is associated with increased macrophage accumulation in the tissue. [8],[9] This accumulation may facilitate local hydroxylation of 25 (OH) D, since macrophages also have the ability to convert circulating 25 (OH) D to 1,25 (OH) D. [10] The specific characteristics of macrophages and their contribution to the local production of 1,25 (OH) D need to be further elucidated, because it remains unclear whether the increased 1,25 (OH) D in adipose tissue is a result of higher uptake of vitamin D or of local conversion secondary to obesity. [11]

In light of this recent evidence, the aim of the present review was to discuss the mechanisms by which the correlation between vitamin D and adipose can occur. There is a need to identify the role and function of the main vitamin D metabolites in obesity and obesity-mediated inflammation, as well as to describe the possible role of vitamin D supplements in the treatment and prevention of obesity.

We searched PubMed databases for review and original articles published in English from 2005 to 2014 by using the following keywords: Vitamin D, hydroxyvitamin D, 25 (OH) D, adipose tissue, adipocytes, inflammation, obesity. Subsequently, the identified references were reviewed and analyzed.


In adipogenesis, a mesenchymal stem cell evolves to a preadipocyte which can then undergo its terminal differentiation and transformation into a mature adipocyte. During the process, the preadipocyte undergoes significant alterations in its morphology, biochemical expression, and cellular functions. Once transformed into mature adipocyte, it is able to transport and synthesize lipids, metabolically respond to insulin, and secrete specific proteins. [12],[13] Vitamin D is emerging as an important target in the adipocyte differentiation process, since it has been suggested that vitamin D may act either by inhibiting or stimulating the expression of the key molecules needed for the differentiation of adipocytes, such as wingless (WNT), CAAT/enhancer-binding protein (EBP) β, and CAAT/EBP α. [14],[15]

In preadipocyte differentiation, some signaling molecules, as members of the WNT family, are released and affect differentiation. [14] Terminal differentiation into mature adipocytes on the other hand, is regulated by CAAT/C/EBPβ followed by C/EBPα, C/EBPd), the master regulator peroxisome proliferator-activated receptor g (PPARg), and sterol regulatory binding protein1. [16],[17] Consequently, these transcriptional factors induce larger expression of genes associated with the adipocyte phenotype, such as lipoprotein lipase, fatty acid binding protein (FABP4) glucose transporter, fatty acid synthase, and adipocyte lipid-binding protein 2, which serves as a late marker of adipogenesis. [18]

The 25 (OH) D stimulates the differentiation of human adipocyte, this may occur through its activation to 1,25 (OH) D. [15] This fact highlights the important function of vitamin D in adipogenesis. In human adipocytes, 1,25 (OH) D promotes adipogenesis since it favors greater expression of the adipogenic markers (such as C/EBPα, C/EBPβ, FABP4 protein, and PPARg). Nevertheless, the in vitro effects of 1,25 (OH) D on adipogenesis are not entirely clear. In nonhuman models, both stimulation [15],[19] and inhibition [20],[21] of adipogenesis in response to 1,25 (OH) D have been reported. In mouse preadipocytes, the active form of vitamin D (1,25 (OH) D) might inhibit adipogenesis by acting on many targets suppressing the expression of C/EBPα and PPARg, specially antagonizing the transaction action of PPARg. [22] Furthermore, it was observed that the induction of PPARg was effectively suppressed by 1,25 (OH) D. [20] In addition, 1,25 (OH) D maintained the level of expression of WNT10B most closely linked to adipogenesis and obesity, resulting in sustained nuclear levels of β-catenin, a suppressor of adipogenesis, thereby suggesting the WNT/β-catenin pathway plays a mediating role for the anti-adipogenic and anti-obesity effects of vitamin D. [20]

In relation to VDR effects on adipogenesis, a positive association between VDR polymorphism and parameters of adiposity such as body mass index (BMI), waist circumference, and abdominal weight has been demonstrated. [2] Polymorphisms in the VDR gene, specifically polymorphisms in the 3'UTR site affecting VDR expression, can suppress the anti-adipogenic effect of vitamin D. [2] In mouse adipocytes, VDR was expressed early in adipogenesis, [23] suggesting that the main local effect of vitamin D on adipogenesis may be the suppression of a premature molecular event the differentiation of preadipocytes. Nevertheless, more studies including in vivo and in vitro adipose tissue models are needed to clarify the specific roles of vitamin D and its metabolites in adipogenesis.

 Obesity, Adipose Tissue, and Vitamin D

Studies on vitamin D status have suggested the existence of an association between obesity and vitamin D deficiency, as obese individuals tend to have low 25 (OH) D concentration. [24],[25] It has been suggested that vitamin D deficiency can be an independent component in the risk for abdominal obesity and obesity in female. [26] There is evidence that increased dietary vitamin D intake and elevated serum 25 (OH) D were correlated to lower adipocyte size and visceral adiposity in women. [27] Results from a clinical trial study with overweight and obese women revealed that 25 (OH) concentration increased after weight loss, those who lost more weight had a higher concentration of vitamin D. [28]

One of the main mechanisms by which vitamin D may act in human adipose tissue is via the expression of vitamin D-metabolizing enzymes such as 25-hydroxylase CYP2J2, CYP27B1, and CYP24. [4],[5],[7] This capacity to metabolize vitamin D locally was demonstrated when, after weight loss in obese subjects, plasma 25 (OH) D increased and expression levels of 25-hydroxylase CYP2J2 and 1α-hydroxylase CYP27B1 declined in the subcutaneous adipose tissue of these subjects. [6] Furthermore, alterations at the VDR locus have been correlated with development and predisposition to obesity during life course. [29] The Taql, Apal, Bsml, and VDR genes were also significantly related with overweight and obesity. [30],[31],[32] BMI appears to be affected for the Bsml VDR polymorphism, where men with the BB genotype had statistically significant greater waist circumference and BMI compared with those carrying the Bb and bb genotypes. [33] These results suggest that subjects with obesity may show modifications in the VDR activity.

Can vitamin D status influence obesity or does obesity influence vitamin D status?

The origin of the typically low vitamin D status seen in obese individuals is not fully understood. However, several hypotheses have been suggested:

Lower-than-normal vitamin D synthesis in these individuals may occur owing to the practice of few outdoor activities and thus lower exposure to sunlight compared with the general population. [34] Lower efficacy of ultraviolet B (UVB) rays for vitamin D synthesis could also be part of the mechanism, as serum 25 (OH) D increased less in obese subjects compared with normal individuals after exposure to the same amount of UVB rays [35]Another more accepted and recognized hypothesis is the sequestration of vitamin D by adipocyte. Elevated storage of vitamin D occurs in the larger-than-normal fat depots prior to conversion into 25 (OH) D [36]There is also the possibility of "dilution." A study of 686 community-dwelling subjects showed that all variability in serum 25 (OH) D concentrations in obesity can be attributed, essentially, to volumetric dilution. After adjusting serum 25 (OH) D concentrations in obese individuals for body composition, the difference between obese and nonobese disappeared [36]Another hypothesis that might explain the low vitamin D levels in obesity centers on mitochondria. Adenosine triphosphate generation after modest exercise is enhanced by vitamin D repletion in vitamin D deficient adults [37]Finally, negative feedback control, whereby excess adipose tissue impairs the vitamin D status from activating energy expenditure. In this mechanism, the leptin stimulates osteocytic fibroblast growth factor 23 (FGF23), FGF23 inhibits renal synthesis of 1α-hydroxylase, and consequently impairs the production of 1,25 (OH) D, creating a negative feedback mechanism. On the other hand, 1,25 (OH) D signaling stimulates adipogenesis and leptin secretion. [34],[38] This pathway could also affect 25 (OH) D production or clearance, but has yet to be further explored and clarified.Although results from several observational studies confirm the correlation between obesity and 25 (OH) D, this by itself is not sufficient to determine that vitamin D deficiency is caused by obesity. The Mendelian randomization studies, a model in which causality might be deduced according to the associations among the genetic variations, can better explain this causality. A recent Mendelian randomization study based on the information from 42,024 subjects found that with every 10% increase in BMI there is result in a 4.2% decline in 25 (OH) D serum levels. [39] On the other hand, the researchers showed that neither 25 (OH) D allele score (based on genes encoding synthesis or metabolism) nor 25 (OH) D concentration was associated with BMI. These results characterize vitamin D deficiency was not a causal component in the progression of obesity. However, the obesity was a causal component in the progression of vitamin D deficiency. [39]

 Adipose Tissue, Vitamin D, and Inflammation

Recent studies have documented that the unusual properties of adipocytes and centrally placed adipose tissue a crucial sites play a role in the generation of inflammatory responses and mediators. Specifically, adipokines can exhibit either proinflammatory or anti-inflammatory properties, thereby contributing to some chronic diseases, such as diabetes mellitus and obesity. [40] Lately, vitamin D function on immune modulator it has been the subject of many studies, particularly in adipose tissue. [3],[41]

In obesity, adipose tissue has a hypertrophic enlargement, which results in blood flow imbalance leading to hypoxia, inflammation, and macrophage infiltration. [42] The increase in the secretion of interleukins 6 and 8 (IL-6, IL-8), resistin, tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant (MCP1), (well-known proinflammatory cytokines) is one of the remarkable characteristics in hypertrophied adipocytes as well as reduced secretion of adiponectin [43] [Figure 1]. The effects of Vitamin D on the adaptive immune system can be observed through T helper cell differentiation, mitogen-activated protein kinase (MAPK) as well as a nuclear factor-kB (NF-kB). [44] Thus, vitamin D suppresses autoimmune disease pathology by regulating the differentiation and activity of CD4Þ T cells, resulting in a more balanced TH1/TH2 response that favors less development of self-reactive T cells and autoimmunity. [45] It has been shown that both 1,25 (OH) D and 25 (OH) D can reduce lipopolysaccharide (LPS)-induced TNF-α and IL-6 production, probably by inhibiting p38 MAPK activation in human monocytes/macrophages. [46]{Figure 1}

Activation of the NF-kB signaling pathway is essential in the signal transduction of proinflammatory cytokines in adipocytes and many other cell types. With the degradation of IkBa protein begins the activation of NFkB, this fact allows the transference of NFkB subunits inside the nucleus as a result regulates downstream transcriptions. [47],[48] Gao et al., (2013) have shown that 1,25 (OH) D can increase IkBa protein abundance in human preadipocytes and that treatment with 1,25 (OH) D led to a reduction in the protein liberation of IL-6 and MCP-1 by human preadipocytes, as well as preadipocyte-induced macrophage migration. [49] Recently, it was observed that 1,25 (OH) D can reverse the macrophage-elicited inhibition of IkBa and up-regulation of p65 NF-kB in differentiated human adipocytes. [7] Concurrently, an inhibitory result of 1,25 (OH) D on TNF-α promoted MCP-1 liberation by human adipocytes has been reported. [50] Mutt et al., investigating cytokine secretion from adipocytes, have shown 1,25 (OH) D to block NFkB p65 translocation to the nucleus in adipocytes [51] [Figure 2]. In vitro treatment with 1,25 (OH) D suppressed macrophage-induced activation of NFkB signaling by increasing IBa expression (2.7-fold, P = 0.005) and reducing NFkB p65 phosphorylation (68%; P = 0.001). Moreover, the study showed that 1,25 (OH) D inhibited expression and release of IL-8 gene from human adipocytes, indicating vitamin D suppression of IL-8 in adipose tissue by the vitamin D. [7] The results of the current study suggest that vitamin D can prevent transcription of proinflammatory genes by reduction of inflammatory responses macrophage-induced in adipocytes as well as inhibits the activation of MAPK and NFkB signaling pathways. Thus, vitamin D can significantly decrease the release of the main proinflammatory molecules at human adipocytes. [7],[49]{Figure 2}

There is insufficient evidence regarding the implications of vitamin D supplementation on inflammatory biomarkers. In mice on a high fat diet, dietary supplementation of vitamin D (0.05 mg/kg of diet) reduced IL-protein amount in the 3T3-L1 cell line and in adipose tissue promoted by LPS. [52] By contrast, in an interventional study, with obese subjects receiving, 7000 international unit daily of oral supplementation of vitamin D over 26 weeks had no effect on inflammatory biomarkers in circulation or in adipose tissue. [53]

 Is Supplementation indicated in Obese Subjects?

A number of studies have shown that vitamin D supplementation can also be beneficial for obese subjects. In a double-blind randomized clinical trial in overweight and obese women, cholecalciferol supplementation after 12 weeks resulted in a significant reduction in the body fat mass of those who received vitamin D compared with those in the placebo group. A significant inverse correlation between alterations in 25 (OH) D concentration and body fat mass was also noted. [54] In addition, vitamin D supplementation increased insulin sensitivity in healthy obese males. [55] Thus, response to vitamin D is dependent on body weight. A study demonstrated that after supplementation, the increase in serum 25 (OH) D levels is lower in overweight or obese women than in women with a normal BMI. [56]

Results of a randomized clinical trial (n = 77) suggest greater fat mass loss in overweight and obese women receiving vitamin D. [54] There was no proof for such an effect in spite of a greater number of subjects, work high vitamin D dose with a larger duration of supplementation. [57],[58] Higher vitamin D requirements in obese individuals have also been implicated. [59],[60] Recently, Mason et al., showed that vitamin D supplementation (2000 IU/day) in women with insufficient vitamin D concentrations at baseline had no effect on body weight or fat loss in postmenopausal women consuming a calorie-restricted diet and following an exercise program. [61] The cited studies highlight the urgency and priority of treating and supervision of the vitamin D deficiency as a way of attenuating the harmful results of excess adiposity on health. It can also be speculated, at a population level, that a decrease in obesity rates may also contribute to a decrease in the frequency of vitamin D insufficiency and deficiency.


Better understanding of the role of vitamin D in the adipose tissue axis in the pathogenesis of obesity, and its metabolic and immune-based complications, is critical. This would optimize long-term health outcomes, as there is a worldwide increase in overweight and obesity. These studies indicate that vitamin D may play a role in the adipose tissue and may be important as in adjuvant in the treatment of obesity. The chronic low-intensity inflammation associated with obesity can also be the target of treatment with vitamin D. Thus, vitamin D is an important nutrient with crucial role in both: In obesity onset (adipose tissue) and in the comorbidities associated with the chronic inflammation, there is a need for longer-term studies focusing on the beneficial effects of vitamin D supplementation in the prevention or treatment of obesity are warranted.

Financial support and sponsorship

CAPES Foundation, Ministry of Education of Brazil, Brasilia- Process- Bex- 6230/14-8.

Conflicts of interest

There are no conflict of interest.


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