Vitamin D, adipose tissue and obesity

Julie Marcotorchino<sup>1,2,3</sup>, Franck Tourniaire<sup>1,2,3</sup>, Jean-François Landrier<sup>1,2,3</sup>

<sup>1</sup> INRA, UMR 1260, F-13385, Marseille, France.

<sup>2</sup> INSERM, UMR 1062, « Nutrition, Obésité et Risque Thrombotique », F-13385, Marseille, France.

<sup>3</sup> Aix-Marseille University, School of Medicine, F-13385, Marseille, France.

Correspondence should be addressed to: Jean-François Landrier, UMR 1260 INRA / 1062 INSERM / Université d'Aix-Marseille, 27 Bd Jean Moulin, 13385 Marseille cedex 05, France. Phone: +33 4 91 29 41 17; Fax: +33 4 91 78 21 01; e-mail address: [jean-francois.landrier@univ-amu.fr](mailto:jean-francois.landrier@univ-amu.fr)
**Abstract**

Epidemiological studies have shown a link between vitamin D deficiency and numerous pathologies such as cancers, immunity diseases, cardiovascular diseases, hypertension, type 2 diabetes and obesity.

Recent studies in vitro and in animal models demonstrated an **impact of** vitamin D on adipose tissue and adipocyte biology. Such observations are of particular interest and provide mechanistic explanations on the relationship between vitamin D deficiency and obesity.

**Introduction**

Vitamin D comes from two sources: exogenous but also endogenous, contrarily to other vitamins [1]. Endogenous synthesis of vitamin D is performed in the epidermis, which is able to produce this vitamin in large quantities after exposure to ultraviolet radiation B. It is synthesized from 7-dehydrocholesterol, a **precursor** of cholesterol, present in the cell membranes of the epidermis [2] (Figure 1). The energy supplied by ultraviolet B allows its transformation into pre-vitamin D3, which is converted in vitamin D3 under the effect of heat, before being released into the circulation. The synthesis of vitamin D is closely related to sun exposure. Classically it has been estimated that 80% to 90% of vitamin D in the body came from sun exposure (159). However, a recent article re-estimates that sun synthesis contributes only to 10-25% of vitamin D supply [3].

Vitamin D can also be provided through the diet. The vitamin D is present in two forms: the vitamin D2 form (ergocalciferol), mainly produced by plants and fungi in particular and the vitamin D3 form (cholecalciferol), synthesized in animals [4]. Only a limited number of foodstuffs contain vitamin D in significant amount. The main sources of vitamin D are fish
liver oils, some fatty fish (sardines, herring, mackerel), the egg yolk or the chicken liver [5].

Vitamin D is also found in small quantities in milk, orange juice, bread or cereals.

## Vitamin D metabolism

Vitamin D is partially absorbed in the distal part of the small intestine, in emulsion with bile salts. Its intestinal absorption occurs not only by passive diffusion but involves, in part, two cholesterol carriers [6]. After absorption, vitamin D reaches the liver via the circulation where it is bound to the vitamin D Binding Protein (VDBP). Vitamins D2 and D3 have a substantially identical metabolism, which depends on the same enzymatic complex in humans. Whatever its origin (endogenous or exogenous), vitamin D is stored in adipocytes. Indeed, in rats, it has been established that fat is the main storage site for vitamin D, where half of it is stored as non-metabolized vitamin D and the other half as polar metabolites, vitamin D esters, and unidentified compounds [7]. In obese patients, vitamin D was measured in subcutaneous adipose tissue [8] and visceral adipose tissue [9] confirming that adipose tissue is also a vitamin D reservoir in humans.

In the liver, vitamin D is hydroxylated on carbon 25 to form 25(OH)-vitamin D3 (25(OH)D). Several enzymes can accomplish this first hydroxylation of 25-hydroxyvitamin D3 (25(OH)D) but CYP2R1 seems to be the key one [10]. After its first hydroxylation, 25(OH)D circulates in the blood, its half-life is relatively long (15 days) and the mean plasma concentration varies between 20 and 50 ng / ml (78-125 nmol / l) [11].

Vitamin D enters in the proximal renal tubule cells, either in its free form (unbound to DBP), or in association with the DBP, where it can be hydroxylated on the carbon 1 to form 1,25(OH)₂D [12]. 1α-hydroxylase (CYP27B1) is highly expressed in the kidney and is
responsible for the conversion of 25(OH)D into 1,25(OH)₂D or calcitriol, which is considered
as the main vitamin D active form. The activity of renal 1α-hydroxylase is regulated by the
parameters of bone and mineral metabolism. It is mainly stimulated by the parathyroid
hormone (PTH). 1,25(OH)₂D is active in different organs. Its half-life is very short (about 4
hours) and its concentration is a thousand times less than the plasmatic vitamin 25(OH)D
concentration.

The metabolism of vitamin D is self-regulated. Indeed, calcitriol induces the expression of 24-hydroxylase (CYP24A1) that converts 25(OH)D and 1,25(OH)₂D into inactive metabolites (i.e. 24,25(OH)₂D and 1,24,25(OH)₃D vitamin D) which are further catabolized into inactive calcitroïc acid [12]. Other enzymes of the cytochrome P450 family, such as CYP3A4, may also degrade calcitriol [10]

Furthermore, many cells express 1α-hydroxylase, which can be locally controlled by signals independent of phosphocalcic metabolism, allowing extra-renal synthesis of 1,25(OH)₂D [13]. In this case, the 25(OH)D enters in these tissues and is hydroxylated into 1,25(OH)₂D to act locally, the excess being metabolized to inactive compounds.

Vitamin D signalization.

Even if few VDR-independent effects of 1,25(OH)₂D have been documented [14], this
hormone mainly exerts its effects by binding to the nuclear vitamin D receptor (VDR), a
member of the nuclear receptor superfamily [15]. It is the only nuclear protein that binds
1,25(OH)₂D with high affinity [16]. The expression of VDR has been demonstrated in almost
all human tissues [13], which means that all cells are potential targets of 1,25(OH)₂D action.
The VDR-1,25(OH)2D complex is associated with the retinoic acid receptor (RXR) [17] and the RXR-VDR-1,25(OH)2D complex binds to the DNA of sites called vitamin D response elements (VDRE), in the promoter region of genes whose expression is either activated or repressed [15]. More than 1000 genes are under the direct or indirect regulation of 1,25(OH)2D, in various physiological process such as cell proliferation, differentiation, apoptosis and angiogenesis [18].

## Vitamin D deficiency and insufficiency

Several factors can lead to vitamin D insufficiency or deficiency. The main one is the reduction of cutaneous synthesis, which may result from a lack of sun exposure (urban life, wearing protective clothing, photoprotection related to skin cancer prevention, sun allergy or photosensitivity) and also from the geographical position (beyond the 35th degree of north latitude, the capacity for synthesis is considered as null or almost null between November and February) [2]. The concentration of 7-dehydrocholesterol in the deeper layers of the skin also decreases with age; a 70 year old person produces 4 times less vitamin D than about 20 years old [19]. The skin pigment (melanin) is a natural sunscreen and increasing the melanin pigmentation can reduce the synthesis of vitamin D as effectively as a sunscreen with an index of protection to 15 [20]. Thus, the prevalence of vitamin D deficiency is higher in patients with dark skin [21]. The synthesis of vitamin D is also decreased by more than 90% by sunscreens which have an index of protection higher than or equal to 15. Certain medications such as steroids and some enzyme inducers activate the nuclear receptor Steroid and Xenobiotic Receptor (SXR) and in this way induce increased expression of CYP3A4, which increases the catabolism of 1,25(OH)2D [1]). Finally, obesity can lead to vitamin D deficiency by reducing its bioavailability through dilution in adipose tissue [22].
Relationship between vitamin D and obesity

Numerous epidemiological studies have suggested a link between vitamin D deficiency and obesity development because obese people tend to have low plasma levels of 25(OH)D [23, 24]. The plasma levels of 25(OH)D levels are inversely correlated to all the parameters of obesity including: BMI, fat mass and waist circumference. Interestingly, increased dietary intake of vitamin D, resulting in higher 25(OH)D plasma levels, is linked to a lower visceral adiposity [25]. The relationship between obesity and the active form of vitamin D (1,25(OH)₂D) is less clear. Recent studies have reported an inverse relationship between 1,25(OH)₂D and BMI and fat mass while older studies show a direct relationship [26, 27]. The origin of this difference is not clear and could result of methodological bias in calcitriol measurement.

Classically the low plasma levels of 25(OH)D have been attributed to the expansion of adipose tissue that would sequestrate vitamin D, thereby reducing its availability in the circulation (218,219). However, a recent study mentioned that lower plasma 25(OH)D in obese population would actually result from the volumetric dilution of 25(OH)D (161). Such decrease of plasma level 25(OH)D could also result from a modification of vitamin D metabolism that occurs during obesity. Indeed, modifications of the expression of genes encoding key enzymes of vitamin D metabolism have been depicted in the adipose tissue of obese people [28].

In human, intervention studies have brought contrasted results. In a recent clinical trial, dietary supplementation with calcium and vitamin D for 16 weeks was associated with a reduction of visceral fat in overweight and obese adults [29]. However, other randomized
clinical trials failed to demonstrate any benefit of a vitamin D supplementation in terms of weight loss [30, 31].

This question remains thus highly controversial and will require well-designed RCT to clarify this point. At the opposite, results generated in vitro and in animal models are consistent with the hypothesis of an impact of vitamin D on adipose tissue biology.

# Effects of vitamin D on the biology of adipose tissue

## Adipogenesis

Many studies have examined the role of 1,25(OH)₂D in proliferation, differentiation and metabolism of 3T3-L1 pre-adipocytes [32, 33]. It has been shown that low concentrations of 1,25(OH)₂D could inhibit adipogenesis and reduce the accumulation of triglycerides. In addition, treatment of preadipocytes with other metabolites of vitamin D, such as 24,25(OH)₂D can also inhibit the differentiation of pre-adipocytes, but only by using supra-physiological concentrations. This would be related to their low affinity for the vitamin D receptor (VDR). One of the early effects of 1,25(OH)₂D on 3T3-L1 cells is increasing mRNA expression of VDR [32]. This suggests that the role of vitamin D in adipogenesis is VDR-dependent. The molecular mechanisms involve a dose-dependent inhibition of a number of genes involved in early and late stages of adipocyte differentiation including CEBPα, PPARγ, lipoprotein lipase (LPL) and adipocyte protein 2/adipocyte specific fatty acid-binding protein (aP2/FABP4), but also sterol-regulatory element-binding protein (SREBP)-1 and fatty acid synthase (FAS) [32]. In addition, the authors observed that the removal of 1,25(OH)₂D after three days of treatment allowed the differentiation process to be restarted. This crucial
observation suggests that the main action of vitamin D on adipogenesis is the removal of a
reversible key molecular event that occurs early in the differentiation process of preadipocyte.
Finally, this study also suggests that 1,25(OH)₂D inhibits adipogenesis by antagonizing
transactivation of PPAR γ and stabilizing the VDR protein.

However these data were not confirmed in human adipocytes where 1,25(OH)₂ enhanced adipocyte differentiation [34]. Interestingly, similar activation of adipogenesis was found in primary mouse preadipocytes (albeit at a more advanced stage of differentiation compared to 3T3-L1 cells), suggesting that the stage of differentiation is particularly important regarding the nature of the effect of 1,25(OH)₂D on adipogenesis.

Metabolism

It is now well established that the vitamin D receptor (VDR) has many activities including the
regulation of the biology and metabolism of adipocytes. An initial study showed that
1,25(OH)2D induced a significant increase in the activity of lipoprotein lipase (LPL) and the
amount of its mRNA in 3T3-L1 adipocytes [35]. At the same time, the fatty acid synthase
(FAS), which catalyzes the lipogenesis is down-regulated by 1,25(OH)2D in 3T3-L1
adipocytes [36]. In vivo studies were undertaken using transgenic mouse models and it has
been shown that mice VDR<sup>-/-</sup> or CYP27B1<sup>-/-</sup> (which are unable to synthesize 1,25(OH)2D) are
resistant to diet-induced obesity [37, 38]. Conversely, overexpression of human VDR in mice
adipose tissue induces an obese phenotype characterized by increased weight and fat mass,
due to a decrease in energy expenditure, reduced fatty acid β-oxidation and lipolysis [39].
These data strongly suggest that VDR and 1,25(OH)2D have an impact on the overall
metabolism by producing particular effects on adipose tissue. However, the specific effects
that could be induced by vitamin D supplementation in this context are still unknown.
In humans, even if vitamin D intake is considered as a predictor of body mass index [40], the impact of vitamin D on regulation of energy metabolism is *not clear*. Baseline 25(OH)D was positively correlated to diet-induced thermogenesis [41]. However, Boon et al. reported no effect of vitamin D supplementation on energy expenditure and fat metabolism, but it is noteworthy that supplementation was conducted for one week only [26].

Inflammation

It is well known that obesity is associated with a low grade inflammatory status, partly caused by an increased production of proinflammatory cytokines by adipose tissue [42]. Several studies conducted on murine 3T3-L1 adipocytes and in human adipocytes have demonstrated that 1,25(OH)₂D increased the expression of inflammatory cytokines and, conversely, inhibited the expression of anti-inflammatory cytokines in both cell types [43, 44]. These results seemed paradoxical in relation to the anti-inflammatory effect of vitamin D well described in many other cell types [45]. Further studies have been undertaken by several groups, which led in 2012 to the publication of four papers relating to the anti-inflammatory effect of vitamin D on adipocytes or preadipocytes (Figure 2). These very consistent results all showed an anti-inflammatory effect of 1,25(OH)₂D whatever the model studied. Indeed, it was shown that 1,25(OH)₂D significantly decreased the release of IL-8, MCP-1 and IL-6 by human preadipocytes [46] and MCP-1 in human adipocytes [47]. These anti-inflammatory effects were associated with inhibition of the NF-κB signaling pathway [48]. Similarly, an anti-inflammatory role of 1,25 (OH)₂D has been demonstrated in murine and human adipocytes. 1,25(OH)₂D was able to decrease the expression of inflammatory markers such as IL-6, IL-1 beta and MCP-1. This effect was accompanied by an improvement in glucose uptake by adipocytes. The molecular mechanisms have been investigated and the involvement
of the VDR and NF-κB signaling pathways and p38 MAP kinases was demonstrated [49]. In addition, these anti-inflammatory properties have also been established in several types of immune cells present in the adipose tissue, such as lymphocytes and macrophages [45]. These results suggest that vitamin D may have a role limited to obesity-associated adipose tissue inflammation, acting both on the inflammatory status of preadipocytes, adipocytes as well as leukocyte infiltration.

**Personal opinion**

Data recently generated by different research group highlight the impact of vitamin D on adipose tissue / adipocyte biology. However, clear confirmation in animal models as well as mechanistic explanations is urgently needed. The effect of vitamin D supplementation alone (i.e. without calcium supplementation) in diet induced obesity mice model has not been investigated so far in terms of weight management and inflammatory status. Several studies have been conducted in transgenic and knockout mice, which provide results in apparent contradiction with epidemiological studies. Some randomized clinical trials have been performed but results remain contrasted, leaving the beneficial role of vitamin D supplementation uncertain. Thus in a near future, we will strongly need well-designed supplementation experiments.

Several key points will require further investigations. It is notably the case of the vitamin D metabolism in adipose tissue / adipocytes, which needs to be clarified. Especially the impact of vitamin D on its own metabolism as well as the effect of physiopathological disorders such as obesity will require studies. These specific points are part of the knowledge urgently required to be more efficient in the design of relevant supplementation studies.
## Highlights

25(OH)D level in plasma are inversely correlated to adiposity and BMI.

Adipose tissue is a physiological storage site for vitamin D.

Vitamin D and metabolites are active on adipocytes and adipose tissue biology.

$1,25(OH)_2D$ generates anti-inflammatory effect and stimulates glucose uptake in adipocytes.

$1,25(OH)_2D$ modulates adipogenesis.

VDR **negatively regulates** of energy homeostasis.
References

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.

2. Holick MF. Vitamin D: a d-lightful solution for health. J Investig Med. 2011 Aug;59(6):872-80.

3. Heaney RP, Armas LA, French C. All-source Basal vitamin d inputs are greater than previously thought and cutaneous inputs are smaller. J Nutr. 2013 May;143(5):571-5.

4. Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hypponen E, Berry J, Vieth R, Lanham-New S. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012 Jun;95(6):1357-64.

5. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30.

6. Reboul E, Goncalves A, Comera C, Bott R, Nowicki M, Landrier JF, Jourdheuil-Rahmani D, Dufour C, Collet X, Borel P. Vitamin D intestinal absorption is not a simple passive diffusion: evidences for involvement of cholesterol transporters. Mol Nutr Food Res. 2011 May;55(5):691-702.

7. Rosenstreich SJ, Rich C, Volwiler W. Deposition in and release of vitamin D3 from body fat: evidence for a storage site in the rat. J Clin Invest. 1971 Mar;50(3):679-87.
8. Blum M, Dolnikowski G, Seyoum E, Harris SS, Booth SL, Peterson J, Saltzman E, Dawson-Hughes B. Vitamin D(3) in fat tissue. Endocrine. 2008 Feb;33(1):90-4.

9. Pramyothin P, Biancuzzo RM, Lu Z, Hess DT, Apovian CM, Holick MF. Vitamin D in adipose tissue and serum 25-hydroxyvitamin D after roux-en-Y gastric bypass. Obesity (Silver Spring). 2011 Nov;19(11):2228-34.

10. Schuster I. Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta. 2011 Jan;1814(1):186-99.

11. Jones KS, Schoenmakers I, Bluck LJ, Ding S, Prentice A. Plasma appearance and disappearance of an oral dose of 25-hydroxyvitamin D2 in healthy adults. Br J Nutr. 2012 Apr;107(8):1128-37.

12. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005 Jul;289(1):F8-28.

13. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008 Oct;29(6):726-76.

14. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8.

15. Carlberg C, Seuter S. A genomic perspective on vitamin D signaling. Anticancer Res. 2009 Sep;29(9):3485-93.

16. Bikle DD, Gee E, Pillai S. Regulation of keratinocyte growth, differentiation, and vitamin D metabolism by analogs of 1,25-dihydroxyvitamin D. J Invest Dermatol. 1993 Nov;101(5):713-8.
17. Issa LL, Leong GM, Eisman JA. Molecular mechanism of vitamin D receptor action. Inflamm Res. 1998 Dec;47(12):451-75.

18. Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010 Dec;9(12):941-55.

19. Krall EA, Sahyoun N, Tannenbaum S, Dallal GE, Dawson-Hughes B. Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J Med. 1989 Dec 28;321(26):1777-83.

20. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1982 Jan 9;1(8263):74-6.

21. Hannan MT, Litman HJ, Araujo AB, McLennan CE, McLean RR, McKinlay JB, Chen TC, Holick MF. Serum 25-hydroxyvitamin D and bone mineral density in a racially and ethnically diverse group of men. J Clin Endocrinol Metab. 2008 Jan;93(1):40-6.

22. Garcia OP, Long KZ, Rosado JL. Impact of micronutrient deficiencies on obesity. Nutr Rev. 2009 Oct;67(10):559-72.

23. Goldner WS, Stoner JA, Thompson J, Taylor K, Larson L, Erickson J, McBride C. Prevalence of vitamin D insufficiency and deficiency in morbidly obese patients: a comparison with non-obese controls. Obes Surg. 2008 Feb;18(2):145-50.

24. Fish E, Beverstein G, Olson D, Reinhardt S, Garren M, Gould J. Vitamin D status of morbidly obese bariatric surgery patients. J Surg Res. 2010 Dec;164(2):198-202.

25. Caron-Jobin M, Morisset AS, Tremblay A, Huot C, Legare D, Tchernof A. Elevated serum 25(OH)D concentrations, vitamin D, and calcium intakes are associated with reduced adipocyte size in women. Obesity (Silver Spring). 2011 Jul;19(7):1335-41.
26. Boon N, Hul GB, Sicard A, Kole E, Van Den Berg ER, Viguerie N, Langin D, Saris WH. The effects of increasing serum calcitriol on energy and fat metabolism and gene expression. Obesity (Silver Spring). 2006 Oct;14(10):1739-46.

27. Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004 Mar;89(3):1196-9.

28. Wamberg L, Christiansen T, Paulsen SK, Fisker S, Rask P, Rejnmark L, Richelsen B, Pedersen SB. Expression of vitamin D-metabolizing enzymes in human adipose tissue-the effect of obesity and diet-induced weight loss. Int J Obes (Lond). 2012 Jul 17.

29. Rosenblum JL, Castro VM, Moore CE, Kaplan LM. Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults. Am J Clin Nutr. 2012 Jan;95(1):101-8.

30. Zittermann A, Frisch S, Berthold HK, Gotting C, Kuhn J, Kleesiek K, Stehle P, Koertke H, Koerfer R. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009 May;89(5):1321-7.

31. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol. 2008 Dec;159(6):675-84.

32. Kamei Y, Kawada T, Kazuki R, Ono T, Kato S, Sugimoto E. Vitamin D receptor gene expression is up-regulated by 1, 25-dihydroxyvitamin D3 in 3T3-L1 preadipocytes. Biochem Biophys Res Commun. 1993 Jun 30;193(3):948-55.
33. Sun X, Zemel MB. Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. Faseb J. 2004 Sep;18(12):1430-2.

34. Nimitphong H, Holick MF, Fried SK, Lee MJ. 25-hydroxyvitamin d(3) and 1,25-dihydroxyvitamin d(3) promote the differentiation of human subcutaneous preadipocytes. PLoS One. 2012;7(12):e52171.

35. Querfeld U, Hoffmann MM, Klaus G, Eifinger F, Ackerschott M, Michalk D, Kern PA. Antagonistic effects of vitamin D and parathyroid hormone on lipoprotein lipase in cultured adipocytes. J Am Soc Nephrol. 1999 Oct;10(10):2158-64.

36. Kong J, Li YC. Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab. 2006 May;290(5):E916-24.

37. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J. Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology. 2009 Feb;150(2):651-61.

38. Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, Sun XJ, Li YC. Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins. Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E820-8.

39. Wong KE, Kong J, Zhang W, Szeto FL, Ye H, Deb DK, Brady MJ, Li YC. Targeted expression of human vitamin D receptor in adipocytes decreases energy expenditure and induces obesity in mice. J Biol Chem. 2011 Sep 30;286(39):33804-10.

40. Kamycheva E, Joakimsen RM, Jorde R. Intakes of calcium and vitamin d predict body mass index in the population of Northern Norway. J Nutr. 2003 Jan;133(1):102-6.
41. Teegarden D, White KM, Lyle RM, Zemel MB, Van Loan MD, Matkovic V, Craig BA, Schoeller DA. Calcium and dairy product modulation of lipid utilization and energy expenditure. Obesity (Silver Spring). 2008 Jul;16(7):1566-72.

42. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005 May;115(5):911-9; quiz 20.

43. Sun X, Zemel MB. Calcium and 1,25-dihydroxyvitamin D3 regulation of adipokine expression. Obesity (Silver Spring). 2007 Feb;15(2):340-8.

44. Sun X, Zemel MB. Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk. J Nutr Biochem. 2008 Jun;19(6):392-9.

45. Guillot X, Semerano L, Saidenberg-Kermanac'h N, Falgarone G, Boissier MC. Vitamin D and inflammation. Joint Bone Spine. 2010 Dec;77(6):552-7.

46. Gao D, Trayhurn P, Bing C. 1,25-Dihydroxyvitamin D3 inhibits the cytokine-induced secretion of MCP-1 and reduces monocyte recruitment by human preadipocytes. Int J Obes (Lond). 2012 Mar;37(3):357-65.

47. Lorente-Cebrian S, Eriksson A, Dunlop T, Mejhert N, Dahlman I, Astrom G, Sjolin E, Wahlen K, Carlberg C, Laurencikiene J, Heden P, Arner P, Ryden M. Differential effects of 1alpha,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes. Eur J Nutr. 2012 Apr;51(3):335-42.

48. Mutt SJ, Karhu T, Lehtonen S, Lehenkari P, Carlberg C, Saarnio J, Sebert S, Hypponen E, Jarvelin MR, Herzig KH. Inhibition of cytokine secretion from adipocytes by 1,25-dihydroxyvitamin D(3) via the NF-kappaB pathway. Faseb J. 2012 Nov;26(11):4400-7.
49. Marcotorchino J, Gouranton E, Romier B, Tourniaire F, Astier J, Malezet C, Amiot MJ, Landrier JF. Vitamin D reduces the inflammatory response and restores glucose uptake in adipocytes. Mol Nutr Food Res. 2012 Dec;56(12):1771-82.
Figures legends

<caption>Figure 1: Vitamin D synthesis, activation and catabolism.</caption>

The vitamin D metabolism. A simplified scheme showing the synthesis of cholecalciferol (vitamin D₃) from 7-dehydrocholesterol upon sunlight exposure and the subsequent two step activation. The first step in the liver which results in the formation of 25-hydroxyvitamin D₃ and the second step in the kidney via CYP27B1 leading to the active hormone 1,25-dihydroxyvitamin D₃.

<caption>Figure 2: Vitamin D decreases inflammatory process in adipocytes and preadipocytes.</caption>

Molecular mechanisms involved in the anti-inflammatory effects of 1,25-dihydroxyvitamin D₃.