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Vitamin D signalling in adipose tissue

Published online by Cambridge University Press:  09 October 2012

Cherlyn Ding ,
Dan Gao ,
John Wilding ,
Paul Trayhurn  and
Chen Bing
Cherlyn Ding
Affiliation:
Obesity Biology Research Group, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, LiverpoolL69 3GA, UK
Dan Gao
Affiliation:
Obesity Biology Research Group, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, LiverpoolL69 3GA, UK
John Wilding
Affiliation:
Obesity Biology Research Group, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, LiverpoolL69 3GA, UK
Paul Trayhurn
Affiliation:
Obesity Biology Research Group, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, LiverpoolL69 3GA, UK Clore Laboratory, University of Buckingham, Hunter Street, BuckinghamMK18 1EG, UK
Chen Bing*
Affiliation:
Obesity Biology Research Group, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, LiverpoolL69 3GA, UK
*
*Corresponding author: Dr C. Bing, fax +44 151 7065802, email [email protected]
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Abstract

Vitamin D deficiency and the rapid increase in the prevalence of obesity are both considered important public health issues. The classical role of vitamin D is in Ca homoeostasis and bone metabolism. Growing evidence suggests that the vitamin D system has a range of physiological functions, with vitamin D deficiency contributing to the pathogenesis of several major diseases, including obesity and the metabolic syndrome. Clinical studies have shown that obese individuals tend to have a low vitamin D status, which may link to the dysregulation of white adipose tissue. Recent studies suggest that adipose tissue may be a direct target of vitamin D. The expression of both the vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes has been shown in murine and human adipocytes. There is evidence that vitamin D affects body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation. Some recent studies demonstrate that vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue. Therefore, vitamin D deficiency may compromise the normal metabolic functioning of adipose tissue. Given the importance of the tissue in energy balance, lipid metabolism and inflammation in obesity, understanding the mechanisms of vitamin D action in adipocytes may have a significant impact on the maintenance of metabolic health. In the present review, we focus on the signalling role of vitamin D in adipocytes, particularly the potential mechanisms through which vitamin D may influence adipose tissue development and function.

Keywords

Vitamin DAdipose tissueAdipocytesInflammationObesity
Type
Horizons in Nutritional Science
Information
British Journal of Nutrition , Volume 108 , Issue 11 , 14 December 2012 , pp. 1915 - 1923
Copyright
Copyright © The Authors 2012

The vitamin D endocrine system has been linked historically to the aetiology of rickets(Reference Mellanby1). Growing evidence suggests that in addition to maintaining Ca homoeostasis and skeletal health(Reference Boyle, Miravet and Gray2, Reference Tanaka, Frank and DeLuca3), vitamin D has pleiotropic actions that can affect multiple organs and metabolic processes, including in the cardiovascular, renal and immune systems(Reference Liu, Stenger and Li4–Reference Zhang, Kong and Deb7). It has been argued that vitamin D deficiency as a global health issue may contribute to the pathogenesis of a number of disorders, including obesity, the metabolic syndrome and type 2 diabetes(Reference Chiu, Chu and Go8–Reference Osei11). Clinical and epidemiological studies show that obese individuals tend to have low vitamin D status(Reference Bell, Epstein and Greene12–Reference Goldner, Stoner and Thompson17). Although vitamin D bioavailability could be reduced in obesity due to increased sequestration by white adipose tissue(Reference Wortsman, Matsuoka and Chen13, Reference Blum, Dolnikowski and Seyoum18), the mechanisms underlying the inverse relationship between adiposity and vitamin D deficiency are largely unknown. Interestingly, recent studies suggest that (white) adipose tissue could be a direct target of vitamin D, and that the hormone may modulate adipose tissue formation and function(Reference Ching, Kashinkunti and Niehaus19–Reference Kamei, Kawada and Kazuki23). Given the multiplicity of functions of white adipose tissue, and the link between dysfunction of the tissue and the pathogenesis of obesity and its co-morbidities, clarifying the role of vitamin D in adipose tissue may lead to public health benefits.

In the present article, we discuss recent advances in our understanding of the interactions between adipose tissue and vitamin D; we also raise questions on vitamin D signalling in adipose tissue, especially the molecular mechanisms underlying the mode of action of the hormone.

The vitamin D system

The two main forms of vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol)(Reference Windaus, Linsert and Lüttringhaus24, Reference Windaus, Schenck and von Weder25); however, vitamin D3 is the only form that is found naturally in human subjects and other animals. Vitamin D3 is synthesised in the skin from 7-dehydrocholesterol through exposure to UVB irradiation(Reference Windaus, Schenck and von Weder25). The resulting pre-vitamin D (precholecalciferol) is converted to vitamin D3 (cholecalciferol) via thermal isomerisation. Although the main source of vitamin D3 is through endogenous synthesis in the skin, the vitamin can also be obtained from the diet and this is important for those who have limited exposure to the sun. The main dietary sources of vitamin D include oily fish, egg yolks and fortified milk. Vitamin D3, whether derived from sunlight or the diet, enters the circulation bound to vitamin D-binding protein and is transported to the liver. Vitamin D3 is hydroxylated in the liver to form 25-hydroxycholecalciferol (25(OH)D3), the major circulating vitamin D metabolite. 25(OH)D3 is then further hydroxylated by a 1α-hydroxylase enzyme (gene: CYP27B1), and this occurs primarily in the kidney to produce 1α,25-dihydroxycholecalciferol (1,25(OH)2D3), the biologically active form of vitamin D. In vivo studies have shown that the catabolism of vitamin D and its metabolites occurs mostly in the liver through a variety of cytochrome P450 enzymes that produce a number of catabolites(Reference Masuda, Byford and Arabian26, Reference Xu, Hashizume and Shuhart27). The 24-hydroxylase (gene: CYP24), a mitochondrial cytochrome P450-containing enzyme, catalyses several steps in 1,25(OH)2D3 degradation through 24-hydroxylation and the formation of calcitrioic acid(Reference Jones, Strugnell and DeLuca28).

Vitamin D receptor

The action of 1,25(OH)2D3 is mediated through the vitamin D receptor (VDR), a member of the nuclear receptor superfamily, which regulates the transcription of many target genes(Reference Demay29, Reference Mangelsdorf, Thummel and Beato30). VDR binds to 1,25(OH)2D3 with high affinity and specificity, which then heterodimerises with a retinoid X receptor(Reference Issa, Leong and Eisman31). Once the heterodimer binds with vitamin D response elements in target genes, a genomic response is generated(Reference Carlberg32, Reference Sutton and MacDonald33). In addition, there is also a plasma membrane VDR which mediates the acute, rapid actions of 1,25(OH)2D3(Reference Huhtakangas, Olivera and Bishop34). VDR has been identified in most human tissues, including in osteoblasts, skin keratinocytes, macrophages, smooth muscle, pancreatic β-cells and epithelial cells(Reference Norman35, Reference Plum and DeLuca36). The ubiquitous expression of VDR may underlie the diverse effects of vitamin D and provide a mechanistic basis for the link between vitamin D deficiency and a number of disorders, including certain types of cancer, inflammatory bowel disease, CVD, diabetes (type 1 and type 2) and the metabolic syndrome(Reference Osei11, Reference Plum and DeLuca36–Reference Yiu, Chan and Yiu39).

Vitamin D deficiency and obesity

Clinically, vitamin D status is normally assessed by measurement of the serum level of 25(OH)D3, the major form of vitamin D in the circulation, with a half life of between 15 and 50 d(40–Reference Holick42). Vitamin D deficiency has been defined as a 25(OH)D3 level of < 20 ng/ml or < 50 nmol/l(Reference Holick43, Reference Dawson-Hughes, Heaney and Holick44). Studies on vitamin D status have suggested that there is a link between vitamin D deficiency and obesity as obese individuals tend to have low serum levels of 25(OH)D3(Reference Goldner, Stoner and Thompson17, Reference Khandalavala, Hibma and Fang45, Reference Fish, Beverstein and Olson46). Serum 25(OH)D3 levels are found to be inversely correlated with measures of obesity, including BMI, fat mass and waist circumference(Reference Ford, Ajani and McGuire47–Reference Jorde, Sneve and Emaus51). Furthermore, a negative association between 25(OH)D3 and visceral fat has been demonstrated in African-Americans with diabetes(Reference Freedman, Wagenknecht and Hairston52). It is suggested that lower levels of circulating 25(OH)D3 in obese individuals could be due to greater sequestration by adipose tissue, reducing its availability in the circulation(Reference Wortsman, Matsuoka and Chen13, Reference Blum, Dolnikowski and Seyoum18). There is evidence that increased dietary vitamin D intake and elevated serum 25(OH)D3 are related to lower visceral adiposity and omental adipocyte size in women undergoing gynaecological surgery(Reference Caron-Jobin, Morisset and Tremblay53). In a recent double-blind, placebo-controlled trial, dietary supplementation with Ca and vitamin D for 16 weeks was associated with a beneficial reduction of visceral fat in overweight and obese adults(Reference Rosenblum, Castro and Moore54).

The relationship between obesity and the active form of vitamin D, 1,25(OH)2D3 (which has a short half life of approximately 15 h residence in the circulation(Reference Jones41)), is less clear, and this is probably due to the dynamic nature of the production and regulation of the active hormone. However, in healthy adults, low serum 1,25(OH)2D3 levels are associated with higher BMI and body fat mass(Reference Parikh, Edelman and Uwaifo14, Reference Frost, Abrahamsen and Nielsen55, Reference Kayaniyil, Vieth and Harris56). Similarly, data from a study of 2000 obese subjects have shown a negative correlation between BMI and serum 1,25(OH)2D3. Taken together, the present evidence strongly suggests that the vitamin D system is altered in obese subjects and this may have implications both for the development of obesity itself and of its co-morbidities.

Vitamin D system in adipose tissue

Recent studies suggest that the key components of the vitamin D system are evident in adipose tissue, and vitamin D could be involved in the function of the tissue(Reference Li, Byrne and Chang21, Reference Narvaez, Matthews and Broun57, Reference Ochs-Balcom, Chennamaneni and Millen58). Expression of the CYP27B1 gene, which encodes the enzyme converting 25(OH)D3 to 1,25(OH)2D3, has been reported in mouse 3T3-L1 preadipocytes and in adipose tissue of Wistar rats(Reference Li, Byrne and Chang21). Recent studies from our group and others have shown that CYP27B1 is expressed by Simpson–Golabii–Beymel Syndrome human adipocytes and preadipocytes(Reference O'Hara, Lim and Mazzatti59, Reference Trayhurn, O'Hara and Bing60) and by human mammary adipocytes(Reference Ching, Kashinkunti and Niehaus19). The CYP24 gene, which encodes the enzyme catalysing 1,25(OH)2D3, is also found to be expressed by murine 3T3-L1 adipocytes and by human adipocytes and preadipocytes(Reference Ching, Kashinkunti and Niehaus19, Reference Li, Byrne and Chang21, Reference O'Hara, Lim and Mazzatti59, Reference Trayhurn, O'Hara and Bing60). Thus, adipocytes could be involved in the local synthesis as well as degradation of biologically active vitamin D.

Although expression of the VDR gene has been reported in mouse white and brown fat and in 3T3-L1 adipocytes(Reference Kamei, Kawada and Kazuki23, Reference Querfeld, Hoffmann and Klaus61), little is known on whether human adipose tissue expresses VDR. We have, however, recently observed that the VDR gene is expressed by human adipose tissue (subcutaneous and visceral) (unpublished results) as well as by human fat cells in culture (preadipocytes and differentiated adipocytes)(Reference O'Hara, Lim and Mazzatti59, Reference Trayhurn, O'Hara and Bing60). Importantly, the bioactivation of 25(OH)D3 to 1,25(OH)2D3 has been demonstrated very recently in human mammary adipocytes, together with the release of 1,25(OH)2D3(Reference Ching, Kashinkunti and Niehaus19). The basal and substrate-induced 1,25(OH)2D3 secretion by mature adipocytes is reported to be higher than with human mammary epithelial cells; these cells are known to be highly efficient at bioactivating 25(OH)D3. This finding suggests that mature adipocytes are capable of taking up 25(OH)D3, converting it to 1,25(OH)2D3 and then releasing the biologically active hormone to the adjacent microenvironment – and possibly to the circulating pool (nevertheless, the kidney is the major source of circulating 1,25(OH)2D3).

Macrophages are known to play a role in vitamin D metabolism, with the ability to convert circulating 25(OH)D3 to 1,25(OH)2D3(Reference Bikle62). Adipose tissue expansion in obesity is associated with an increase in macrophage accumulation in the tissue(Reference Xu, Barnes and Yang63, Reference Weisberg, McCann and Desai64), which may facilitate the local hydroxylation of 25(OH)D3. However, the specific characteristics of adipose tissue macrophages and their potential contribution to the local production of 1,25(OH)2D3 need to be clarified.

Data on the actual 1,25(OH)2D3 content of human adipose tissue are very limited. In a small study of seventeen morbidly obese subjects undergoing gastric bypass surgery, the 1,25(OH)2D3 concentrations measured by liquid chromatography–MS (LC/MS) were much higher (>10-fold) in abdominal subcutaneous fat than in serum(Reference Blum, Dolnikowski and Seyoum18). Whether there is a rise in 1,25(OH)2D3 levels in adipose tissue, either by increased uptake or through local conversion in the obese state, is not known. Collectively, these findings suggest that human adipose tissue could well be a target for vitamin D, through endocrine as well as autocrine/paracrine actions of the hormone (Table 1).

Table 1 Vitamin D-related gene expression identified in adipose tissue and adipocytes

VDR, vitamin D receptor; SGBS, Simpson–Golabii–Beymel syndrome.

Role of vitamin D in adipogenesis

Vitamin D and its receptor VDR have been implicated in the modulation of preadipocyte differentiation into adipocytes (adipogenesis)(Reference Blumberg, Tzameli and Astapova65). The differentiation of 3T3-L1 (and other) preadipocytes is a highly controlled process through sequential induction of transcription factors that regulate the expression of adipocyte-specific markers. During adipogenesis, a series of cellular events begins with the rapid expression of CCAAT/enhancer-binding protein β (C/EBPβ), followed by the expression of C/EBPα, PPARγ and sterol-regulatory element-binding protein 1 (SREBP1)(Reference Mandrup and Lane66). As a result, there is increased expression of genes that produce the adipocyte phenotype, such as lipoprotein lipase, and adipocyte lipid-binding protein 2, which serves as a late marker of adipogenesis(Reference Christy, Yang and Ntambi67, Reference Dani, Amri and Bertrand68). During differentiation, the expression of genes encoding lipogenic enzymes such as fatty acid synthase is highly induced and de novo fatty acid synthesis increases enormously(Reference Madsen, Petersen and Kristiansen69).

There is some evidence that 1,25(OH)2D3 inhibits 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and this is in line with its inhibitory effect on the expression of adipogenic transcription factor (C/EBPβ, PPARγ and SREBP1) genes and of the downstream adipocyte markers (lipoprotein lipase, adipocyte lipid-binding protein 2 and fatty acid synthase), although 1,25(OH)2D3 does not block the induction of C/EBP(Reference Kong and Li22). The linkage between 1,25(OH)2D3 and adipocyte lipogenesis has also been supported by a study which demonstrated that the hormone strongly increased mRNA levels of insulin-induced gene-2 (Insig-2), a factor which blocks fatty acid synthesis in mature 3T3-L1 adipocytes and inhibits preadipocyte differentiation(Reference Lee, Lee and Choi70). During the differentiation of human mammary preadipocytes, exposure to 25(OH)D3 or 1,25(OH)2D3 led to a significant reduction in lipid accumulation at day 7 but not at day 14, suggesting that vitamin D metabolites may inhibit the initiation of human preadipocyte differentiation(Reference Ching, Kashinkunti and Niehaus19). Furthermore, in addition to reducing protein expression of C/EBPα, PPARγ and adipocyte lipid-binding protein 2 by 1,25(OH)2D3 alone, the combination of 1,25(OH)2D3 with genistein enhanced suppression of adipocyte lipid-binding protein 2 expression and lipid accumulation in 3T3-L1 adipocytes(Reference Rayalam, Della-Fera and Ambati71). The effects of 1,25(OH)2D3 metabolites on adipogenesis may involve VDR, as 1,25(OH)2D3 combined with genistein significantly increased VDR protein expression(Reference Rayalam, Della-Fera and Ambati71).

VDR has been shown to be expressed at the early stage of adipogenesis in 3T3-L1 cells and its expression levels are maintained by 1,25(OH)2D3 during the course of adipocyte differentiation(Reference Blumberg, Tzameli and Astapova65). In the presence of 1,25(OH)2D3, VDR inhibits adipogenesis by reducing C/EBPβ mRNA and C/EBPβ nuclear protein levels at a critical stage of differentiation(Reference Blumberg, Tzameli and Astapova65). In addition, 1,25(OH)2D3 induces the up-regulation of C/EBPβ core-repressor, eight twenty-one (ETO), which would further restrain the activity of remaining C/EBPβ(Reference Blumberg, Tzameli and Astapova65). A recent study has shown a positive association between VDR polymorphisms and the parameters of adiposity(Reference Ochs-Balcom, Chennamaneni and Millen58). VDR gene variants with polymorphisms on the 3′ UTR site, which affect the expression of VDR, are postulated to suppress the anti-adipogenic effect of vitamin D(Reference Ochs-Balcom, Chennamaneni and Millen58). Interestingly, a role for unliganded VDR in adipogenesis has been proposed, as VDR overexpression suppresses 3T3-L1 preadipocyte differentiation in the absence of 1,25(OH)2D3(Reference Kong and Li22). In contrast, the data from another study suggest that the unliganded VDR is required for lipid accumulation, as VDR knockdown with siRNA delays and prevents this process(Reference Blumberg, Tzameli and Astapova65). However, in vivo studies on VDR function suggest that VDR could promote adipogenesis. Mice with a global VDR knockout had little fat mass and higher rates of β-oxidation in adipose tissue in comparison with wild-type controls(Reference Wong, Szeto and Zhang72). Thus, additional studies, including adipose tissue-specific knockout models, are required to clarify the function of VDR in adipogenesis.

Vitamin D and lipid metabolism

There is some evidence that vitamin D could be involved in lipid mobilisation and utilisation in adipose tissue. An early study observed that 1,25(OH)2D3 induced a significant increase in lipoprotein lipase activity and of its mRNA level in 3T3-L1 adipocytes(Reference Querfeld, Hoffmann and Klaus61). Concurrently, fatty acid synthase, which catalyses adipocyte lipogenesis, is down-regulated by 1,25(OH)2D3 in 3T3-L1 cells(Reference Kong and Li22). However, in vivo functional studies of VDR suggest that the receptor could inhibit lipid mobilisation and utilisation. VDR-null mice were reported to be resistant to high-fat diet-induced obesity, probably due to increases in fatty acid β-oxidation in white adipose tissue and the expression of uncoupling proteins in brown fat and of overall energy expenditure(Reference Wong, Szeto and Zhang72). On the other hand, targeted expression of VDR in adipocytes induces obesity in mice without changes in food intake, which is mainly caused by a marked decrease in energy expenditure together with reduced lipolysis and β-oxidation in adipose tissue(Reference Wong, Kong and Zhang20). In addition, the expression of genes involved in lipid metabolism, including hormone-sensitive lipase, adipose TAG lipase and uncoupling proteins 1, 2 and 3, is suppressed in VDR transgenic mice(Reference Wong, Kong and Zhang20).

Data on the effects of vitamin D in lipid metabolism in human subjects are scarce. A study of a small number of non-obese healthy subjects (n 10) has shown that vitamin D supplementation (2000 IU cholecalciferol/d), together with a low dietary Ca intake for 7 d, had no effect on energy expenditure, substrate metabolism or the expression of genes related to fat metabolism, such as hormone-sensitive lipase, fatty acid synthase and uncoupling protein 2 in adipose tissue, despite a significant increase in serum 1,25-OH2D3 levels(Reference Boon, Hul and Sicard73). These negative results could be due to the relatively short period (7 d) of treatment or because supplementation with cholecalciferol has little effect on healthy subjects who have adequate levels of vitamin D. Taken together, the present data are inconclusive and additional models and human studies are required to clarify the role of vitamin D metabolites in lipid metabolism.

Vitamin D and adipokine production

In addition to fuel storage, adipose tissue as an endocrine organ secretes a variety of bioactive proteins, and importantly a number of these adipokines, including adiponectin, TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1), are directly involved in inflammation(Reference Trayhurn, Bing and Wood74, Reference Trayhurn and Wood75). There are as yet few studies that have examined the possible role of vitamin D in the modulation of adipokine production. It has been shown that mice lacking the VDR or CYP27B1 genes have reduced levels of serum leptin(Reference Narvaez, Matthews and Broun57). In a Middle-Eastern population of non-obese young subjects, serum 25(OH)D3 was found to be positively correlated with adiponectin levels, though inversely associated with several metabolic risk factors, suggesting a possible link between vitamin D status and circulating adiponectin concentrations(Reference Gannagé-Yared, Chedid and Khalife76).

There is some evidence that vitamin D3 may directly regulate adipokine expression and secretion by adipocytes. An in vitro study has shown that treatment with 1,25(OH)2D3 (10 nm) up-regulated the expression of the macrophage inhibitory factor (MIF), IL-6 and MCP-1 genes in 3T3-L1 adipocytes, and increased MIF mRNA levels in human adipocytes(Reference Sun and Zemel77). However, a recent in vivo study has reported that vitamin D supplementation reduced IL-6 protein content in adipose tissue of mice fed a high-fat diet, and 1,25(OH)2D3 (100 nm) inhibited LPS-induced IL-6 production by 3T3-L1 adipocytes(Reference Lira, Rosa and Cunha78). More recently, 1,25(OH)2D3 (100 nm) has been shown to inhibit the release of MCP-1 and adiponectin by human adipocytes(Reference Lorente-Cebrian, Eriksson and Dunlop79). The discrepancy between results might be due to the different doses used in these studies. Therefore, further work is needed to elucidate whether 1,25(OH)2D3 has a role in modulating the production of adipokines involved in inflammation.

Vitamin D and inflammation in adipose tissue

The potential role of vitamin D in modulating inflammation in obesity and other chronic diseases has received increasing attention. Evidence has accummulated that 1,25(OH)2D3 has potent immunoregulatory effects, such as inhibiting the production of IL-6, IL-8 and interferon-γ by peripheral blood mononuclear cells from psoriatic patients(Reference Inoue, Matsui and Nishibu80). It has also been shown that 1,25(OH)2D3 down-regulates the gene and protein expression of toll-like receptor (TLR) 2 and TLR-4 in human monocytes(Reference Do, Kwon and Park81). 1,25(OH)2D3 also suppresses peripheral blood mononuclear cells’ proliferation and induces apoptosis in peripheral blood mononuclear cells of healthy subjects and inflammatory bowel disease patients(Reference Martinesi, Treves and d'Albasio82). Both 1,25(OH)2D3 and 25(OH)D3 have been shown to reduce lipopolysaccharide-induced TNF-α and IL-6 production, probably by inhibiting p38 MAPK activation in human monocytes/macrophages(Reference Zhang, Leung and Richers83). Conversely, 1,25(OH)2D3-deficient T-cells isolated from CYP27B1 knockout mice are predisposed to overexpress IL-17(Reference Bruce, Yu and Ooi84), while VDR-null mice display a failure of T-cell homing to the gut with low levels of IL-10 in inflammatory bowel disease(Reference Yu, Bruce and Froicu85). Furthermore, in peripheral blood mononuclear cells from type-2 diabetic patients having a proinflammatory profile, 1,25(OH)2D3 is reported to act in an anti-inflammatory manner to decrease the expression of TNF-α, IL-1, IL-6 and IL-8(Reference Giulietti, van Etten and Overbergh86). In vivo, aged mice treated with vitamin D3 showed a significant improvement in visual function by reducing retinal inflammation and amyloid-β accumulation(Reference Lee, Rekhi and Kam87).

With adipocyte hypertrophy in obesity, there is a marked increase in the synthesis and release of proinflammatory mediators (e.g. TNF-α, IL-6, IL-8 and MCP-1), and this contributes to the raised circulating levels as well as to the tissue inflammation(Reference Fontana, Eagon and Trujillo88, Reference Skurk, Alberti-Huber and Herder89). Adipose tissue inflammation, characterised by increased infiltration of macrophages and other immune cells, is a central pathological process in adipose tissue dysfunction(Reference Cinti, Mitchell and Barbatelli90, Reference Lolmede, Duffaut and Zakaroff-Girard91). Work from our group and others has demonstrated that macrophage-conditioned medium potently stimulates the release of proinflammatory factors (e.g. MCP-1, IL-8, chemokine (C–C motif) ligand 5 (CCL-5) and IL-6) and a number of proteins involved in extracellular matrix remodelling from human preadipocytes and adipocytes; these factors may induce inflammation, fibrosis and insulin resistance in adipose tissue(Reference O'Hara, Lim and Mazzatti59, Reference Lacasa, Taleb and Keophiphath92–Reference Gao and Bing95). The immunoregulatory effects of 1,25(OH)2D3 suggest that the hormone may also modulate the inflammatory response in adipose tissue. Very recently, we have shown that treatment with 1,25(OH)2D3 (10 and 100 nm) led to a reduction in the protein release of MCP-1 and IL-6 by human preadipocytes, as well as preadipocyte-induced macrophage migration(Reference Gao, Trayhurn and Bing96). Concurrently, an inhibitory effect of 1,25(OH)2D3 on TNF-α-stimulated MCP-1 release by human adipocytes has been reported(Reference Lorente-Cebrian, Eriksson and Dunlop79).

Activation of the NF-κB signalling pathway is essential in the signal transduction of proinflammatory cytokines in many cell types, including adipocytes(Reference Gao and Bing95, Reference Fujihara, Antunes and Mattar97, Reference Chen, Kong and Sun98). NF-κB activation involves the degradation of IκBα protein and translocation of p65 into the nucleus(Reference Bonizzi and Karin99). Our recent work has shown that 1,25(OH)2D3 can increase IκBα protein abundance in human preadipocytes(Reference Gao, Trayhurn and Bing96). Blocking of NF-κB activation by 1,25(OH)2D3 has also been reported in mesangial cells, as 1,25(OH)2D3 can stabilise IκBα, leading to an inhibition of p65 NF-κB nuclear translocation(Reference Zhang, Yuan and Sun100). Very recently, we have observed that 1,25(OH)2D3 is able to reverse macrophage-elicited inhibition of IκBα and up-regulation of p65 NF-κB in differentiated human adipocytes (unpublished results). Overall, 1,25(OH)2D3 appears to be anti-inflammatory and it may ameliorate macrophage-induced inflammation in adipose tissue (Fig. 1).

Fig. 1 Proposed mechanism of vitamin D3 signalling in adipocytes. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) may be transferred into the adipocyte (from the circulation or adjacent cells) or 25(OH)D3 taken up from the circulation and hydroxylated in the fat cell by 1α-hydroxylase. 1,25(OH)2D3 acts to inhibit the phosphorylation of p38 MAPK and the activation of NF-κB signalling, with enhanced IκBα expression while reduced phosphorylation of p65, in human adipocytes. As a result, gene expression and protein release of proinflammatory mediators (i.e. monocyte chemoattractant protein-1 (MCP-1) and IL-6) by fat cells are reduced, leading to decreased recruitment of monocytes/macrophages and overall inflammation within adipose tissue.

Vitamin D and insulin resistance

Several clinical studies have associated low vitamin D status with the development of insulin resistance in adults(Reference Chiu, Chu and Go8, Reference Gannagé-Yared, Chedid and Khalife76, Reference Scragg, Holdaway and Singh101) and children(Reference Parikh, Guo and Pollock102, Reference Olson, Maalouf and Oden103). Higher basal levels of 25(OH)D3 have been found to predict better β-cell function and lower glycaemia in subjects at risk for type 2 diabetes(Reference Kayaniyil, Retnakaran and Harris104). In rats, vitamin D deficiency impairs insulin release from the pancreas and reduces glucose tolerance, which is partially reversed following treatment with 1,25(OH)2D3(Reference Billaudel, Bourlon and Sutter105, Reference Cade and Norman106). A recent clinical trial has shown that cholecalciferol (2000 IU daily) supplementation for 16 weeks improved β-cell function in adults at high risk of diabetes(Reference Mitri, Dawson-Hughes and Hu107). In type 2 diabetic patients with vitamin D deficiency, daily intake of a vitamin D-fortified yogurt drink increased serum 25(OH)D3 levels and improved glycaemic status(Reference Nikooyeh, Neyestani and Farvid108). Therefore, vitamin D may have an effect on insulin secretion from pancreatic β-cells and further work in this area is warranted.

A potentially beneficial effect of vitamin D on insulin sensitivity has been proposed, as 1,25(OH)2D3 treatment increased insulin receptor mRNA levels and insulin-stimulated glucose transport in U-937 promonocytic cells, possibly via the up-regulation of phosphatidylinositol 3-kinase activity(Reference Maestro, Molero and Bajo109). Adipose tissue, in addition to skeletal muscle and liver, is a key organ exhibiting insulin resistance in obesity(Reference Hotamisligil110). Although adipose tissue only accounts for approximately 10 % of insulin-stimulated whole-body glucose uptake, the reduction in insulin sensitivity of adipocytes increases NEFA release into the circulation, which may induce hepatic and muscle insulin resistance(Reference Smith111). In streptozotocin-induced diabetic rats, 1,25(OH)2D3 treatment has been reported to normalise the number of insulin receptors and improve the insulin response to glucose transport in epididymal adipocytes(Reference Calle, Maestro and Garcia-Arencibia112). However, whether vitamin D metabolites have beneficial effects on glucose transport and insulin action in human adipose tissue remains to be investigated.

Conclusions

In conclusion, the vitamin D system has multiple physiological functions beyond its classical role in Ca homoeostasis and bone metabolism. Data from clinical studies have indicated that vitamin D deficiency is associated with several diseases, including obesity and type 2 diabetes. Emerging evidence suggests that adipose tissue could be a target for vitamin D actions, as the CYP27B1 and VDR genes are expressed by adipocytes of both rodents and human subjects. Recent in vitro studies suggest that 1,25(OH)2D3 may inhibit adipogenesis by suppressing the expression of the key adipogenic transcription factors and reducing lipid accumulation in adipocytes. Moreover, VDR overexpression in 3T3-L1 cells inhibits preadipocyte differentiation, and VDR polymorphisms are associated with increased adiposity in human subjects. However, functional studies of VDR in vivo have produced opposite results, as VDR-null mice exhibit a lean phenotype with reduced fat mass. Consistent with its immunomodulatory effects in other cell types, vitamin D appears to be anti-inflammatory in adipose tissue. This is particularly demonstrated by the inhibition of the expression and release of MCP-1 from human adipocytes by 1,25(OH)2D3. Therefore, it is probable that vitamin D has a regulatory role in adipose tissue function in health and disease. Further experimental and translational studies are needed to unravel the signalling role of vitamin D in adipose tissue, particularly its putative link to adipocyte dysfunction in obesity.

Acknowledgements

The authors declare that they have no conflicts of interest. C. B. and C. D. wrote the draft of the article, with subsequent additions and revisions from D. G., J. W. and P. T.; C. B. prepared the final version. The present work was supported by the Medical Research Council (G0801226) and the University of Liverpool.

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Figure 0

Table 1 Vitamin D-related gene expression identified in adipose tissue and adipocytes

Figure 1

Fig. 1 Proposed mechanism of vitamin D3 signalling in adipocytes. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) may be transferred into the adipocyte (from the circulation or adjacent cells) or 25(OH)D3 taken up from the circulation and hydroxylated in the fat cell by 1α-hydroxylase. 1,25(OH)2D3 acts to inhibit the phosphorylation of p38 MAPK and the activation of NF-κB signalling, with enhanced IκBα expression while reduced phosphorylation of p65, in human adipocytes. As a result, gene expression and protein release of proinflammatory mediators (i.e. monocyte chemoattractant protein-1 (MCP-1) and IL-6) by fat cells are reduced, leading to decreased recruitment of monocytes/macrophages and overall inflammation within adipose tissue.