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Background: Vitamin D deficiency has been often observed in obese persons. One of the mechanisms suggested for low vitamin D status in obesity was decreased bioavailability of vitamin D (VD) due to sequestration in adipose tissue. However, only few studies have investigated this mechanism via quantifying vitamin D levels from tissues from the obese. Methods: Six-wk-old C57BL/6 mice were fed 10 or 45% kcal fat (CON or HFD) diets containing 50, 1000 or 25,000 IU vitamin D3/kg diet (LVd, CVd or HVd) for 13 wks. Serum 25-hydroxyvitamin D (25(OH)D) levels were determined by radioimmunoassay and liver and adipose tissue cholecalciferol (VD3) and 25-hydrocholecalciferol (25(OH)D3) levels were measured by LC-MS/MS. mRNA levels of jejunal Mttp, Cd36, Sr-b1, Npc1l1, and Abca1 and liver and adipose tissue 25-hydroxylases (Cyp2r1 and Cyp27a1) were determined by real-time PCR. Results: Serum 25(OH)D levels were affected by dietary vitamin D content but differential effects were observed between HFD and CON groups. When vitamin D intake was at a supplementary level, the HFD-HVd group had lower serum 25(OH)D levels than the CON-HVd group, while there was no significant difference between the HFD and CON groups fed LVd or CVd. Total amount of VD3 in liver and adipose tissue were significantly higher in HFD-HVd group compared with the CON-HVd group. However, no difference in total amount of tissue VD3 was observed between the CON and HFD groups fed CVd. In jejunum, mRNA levels of Mttp and Abca1 were significantly higher in HFD groups than CON groups. There was no difference in mRNA levels of liver 25-hydroxylases by both dietary fat amount and vitamin D content. Conclusion: A significant amount of VD3 seemed to be stored in the liver and adipose tissue when dietary vitamin D is at a supplementation level; thus excess body adiposity could contribute to relatively low serum 25(OH)D level when vitamin D was supplemented. [ABSTRACT FROM AUTHOR]

To determine the effect of age on susceptibility to azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and its underlying mechanism, young and old mice were injected with AOM weekly for 4 or 5 weeks and euthanized 5 or 6 weeks later. Given the same (12 or 15) mg/kg body weight dose of AOM, old mice had significantly more ACF than young mice. However, given the same total dose of AOM (to avoid confounding effect of higher dose to heavier old mice), at a low total dose (1.5 mg) there was no age difference, but at higher total doses (1.8 and 2.2 mg) young mice had significantly more ACF than old mice. These results indicate that the age-related susceptibility to AOM differs depending on whether administration of the carcinogen is based on weight or total dose. These age differences are not due to variations in cyclooxygenase-2 expression, cell proliferation, or AOM hydroxylase activity. [ABSTRACT FROM AUTHOR]

Vitamin E, part of the body's primary lipid-soluble defense against free radicals and reactive oxygen molecules, has been suggested to reduce the risk for some cancers. However, the role of vitamin E in the etiology and prevention of colon cancer, especially in the highest risk group, the aged, is not clear. Thus, this study was conducted to elucidate the effect of vitamin E supplementation on susceptibility to colon cancer by examining azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation, a surrogate biomarker of colon cancer. Young (3-4 mo) and old (19-20 mo) C57BL/6JNIA mice were fed either a control diet (30 mg dl-alpha-tocopheryl acetate/kg diet) or a vitamin E-supplemented diet (500 mg dl-alpha-tocopheryl acetate/kg diet) for 16 wk. After 6 wk of dietary supplementation, young and old mice were injected with saline or AOM weekly for 5 wk to receive the same total dose of AOM (2.2 mg) and killed 10 wk after the first AOM injection. Vitamin E supplementation had no effect on the number of AOM-induced ACF in young or old mice. In addition, vitamin E supplementation did not have an effect on splenocyte interferon-gamma, interluekin-6 and tumor necrosis factor-alpha levels, natural killer cell killing activity or colonic cell proliferation in young or old mice. Thus, alpha-tocopherol does not seem to affect the initiation and early promotion stages of AOM-induced colon carcinogenesis in young or old mice. Whether vitamin E supplementation might be effective in reducing AOM-induced colon tumors is unclear. [ABSTRACT FROM AUTHOR]

• Natural killer (NK) cell activity is low and NK cell maturation is suppressed in diabetic mice. • Interferon-γ production of splenocyte is low in diabetic mice. • Transforming growth factor-β expression in spleen is high in diabetic mice. • Enhanced NK cell activity may be associated with changes in proportion of mature NK cells. • Vitamin D supplementation enhanced interleukin-12 production. • Vitamin D supplementation enhanced Bcl2 and Tbx21 expression in NK cells. Type 2 diabetes mellitus negatively affects the immune system, resulting in reduced natural killer (NK) cell activity. Vitamin D has been shown to regulate innate and adaptive immune cells. However, the effects of vitamin D on NK cells remain inconclusive, especially in the context of diabetes. We hypothesized that dietary vitamin D 3 supplementation can enhance NK cell activity in diabetic mice. Therefore, we investigated the effects of dietary vitamin D 3 on NK cell activity in control and diabetic mice and explored the mechanisms of NK cell activity modulation by vitamin D 3. Control (CON) and diabetic mice (db/db) were randomly divided into 2 groups, then fed either a control diet (948 IU vitamin D 3 /kg diet, vDC) or a diet supplemented with vitamin D 3 (9,477 IU vitamin D 3 /kg diet, vDS) for 8 weeks. Diabetic mice exhibited lower NK cell activity than control mice. The vDS group had significantly higher NK cell activity than the vDC group in both control and diabetic mice. The vDS group had a higher percentage of CD11b single-positive NK cells than the vDC group (CON-vDS 34%; db/db-vDS 30%; CON-vDC 27%; db/db-vDC 22%). The intracellular expression of splenic TGF-β was significantly higher in the db/db group than in the CON group. Overall, vDS group had higher Bcl2 and Tbx21 mRNA expressions than the vDC group. In conclusion, the present study shows that NK cell activity is impaired under diabetic conditions, possibly due to the reduced percentage of mature NK cells. Moreover, NK activity is enhanced by dietary supplementation in both control and diabetic mice that may be associated with changes in the proportion of mature NK cells. The purpose of the study is to investigate the effects of vitamin D on NK cell activity in diabetic conditions. The results showed that diabetic mice showed impaired NK cell activity with lower percentage of mature NK cells and NKG2D expression. However, dietary vitamin D 3 -supplementated group showed enhanced NK cell activity in diabetic mice, along with increased production of NK-stimulating cytokines and increased levels of mRNAs associated with NK cell maturation.Abbreviations: Bcl-2, B-cell lymphoma/leukemia-2; CD, cluster of differentiation; IFN-γ, Interferon gamma; IL, interleukin; NK cells, Natural killer cells; NKG2D, Natural killer group 2D; Tbx21, T-box transcription factor 21; TGF-β, Transforming growth factor beta. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Anthocyanins are naturally occurring polyphenolic pigments in plants that have been shown to decrease weight gain and insulin resistance in mice-fed high-fat diets. We investigated the effects of anthocyanins on cell growth, differentiation, and lipolysis in 3T3-L1 cells to test our hypothesis that anthocyanins could reduce adipose tissue mass by acting directly on adipocytes. Anthocyanin extracts from black soybeans were used and composed of 3 of the following major anthocyanins: cyanidine-3-O-glucoside (68.3%), delphinidin-3-O-glucoside (25.2%), and petunidin-3-O-glucoside (6.5%). Treatment with 12.5 and 50 μg/mL of black soybean anthocyanins exhibited inhibitory effects on the proliferation of both preconfluent preadipocytes (P < .01) and maturing postconfluent adipocytes (P < .01). In fully differentiated adipocytes, the number of viable cells was reduced by black soybean anthocyanins (P < .01). Treatment with 50 μg/mL of black soybean anthocyanins slightly increased epinephrine-induced lipolysis but decreased the basal lipolysis of fully differentiated adipocytes (P < .05). Black soybean anthocyanins also reduced lipid accumulation and suppressed the expression of the peroxisome proliferator–activated receptor γ, a major transcription factor for the adipogenic gene (P < .01). These results suggest that black soybean anthocyanins inhibit adipocyte differentiation and basal lipolysis, which may contribute to their antiobesity and antidiabetic properties. [Copyright &y& Elsevier]

Abstract: An increased risk of iron deficiency has been reported in obese individuals. We investigated hepatic iron status and serum levels of both adipokines and inflammatory markers in obese mice to test the hypothesis that high-fat-diet (HFD)–induced obesity leads to reduced iron storage associated with inflammation. Four-week-old C57BL mice were fed a HFD containing 60% energy from fat for 16 weeks and were compared with mice on a control diet with 10% energy from fat. The HFD group had significantly higher levels of leptin (43.7 ng/mL in control, n = 16 vs 104.3 ng/mL in HFD, n = 17; P < .001) and significantly lower amounts of high-molecular-weight adiponectin (4.80 μg/mL in control, n = 16 vs 3.67 μg/mL in HFD, n = 18; P = .002) compared with the control group. Higher serum amyloid A levels in the HFD group (60.4 μg/mL in control, n = 17 vs 117.9 μg/mL in HFD, n = 18; P < .001) suggest inflammation in the HFD-induced obese animals. The HFD group had lower hepatic nonheme iron (3.12 μg/mg protein in control, n = 17 vs 0.869 μg/mg protein in HFD, n = 16; P < .001). Expression of hepcidin messenger RNA (mRNA) was only 54% of the control levels in HFD mice (P = .016). However, the ratio of hepcidin mRNA expression to nonheme iron was 2.5-fold higher in the HFD compared with the control animals. Hepcidin is a homeostatic regulator of iron metabolism that restricts intestinal iron absorption and is also known as a mediator of inflammation. Increased serum amyloid A levels and a higher ratio of hepatic hepcidin mRNA expression to nonheme iron suggest that lower hepatic iron status in obese animals might be associated with inflammation. [Copyright &y& Elsevier]

Inflammatory bowel disease (IBD) often accompanies vitamin D deficiency, and vitamin D supplementation ameliorates IBD symptoms in animal models and humans. Because altered vitamin D metabolism has been reported in obesity, we hypothesized that the effects of vitamin D on the development of IBD would be different between obese and control mice. Five-week-old male C57BL/6N mice were divided into 4 groups and fed a diet differing in fat content (10% or 45%, normal diet [ND] or high-fat diet [HFD]) and vitamin D content (1000 or 10 000 IU/kg of diet, vDC or vDS) for 14 weeks. At week 13, colitis was induced by administration of 2% dextran sodium sulfate for 7 days. Histology score tended to be lower in the HFD-vDS group than HFD-vDC group, but there was no effect of vitamin D on the ND group. Colonic Cldn1 and Cyp27b1 mRNA levels were higher in the HFD-vDS than HFD-vDC group, but these effects of vitamin D were not observed in the ND group. The serum 25-hydroxy vitamin D levels were negatively correlated with the histology score in the HFD group but not in the ND group. Overall, these results suggest that vitamin D supplementation partially prevents the histological damage of the colon in obese mice but not in control mice. This effect might be mediated by increased colonic Cyp27b1 levels, leading to upregulation of local 1,25-dihydroxy vitamin D production. [ABSTRACT FROM AUTHOR]

Altered regulation of vitamin D metabolites, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25[OH] 2 D), was observed in high-fat diet (HFD)–induced obesity. We hypothesized that these HFD-induced changes in vitamin D metabolism would be reversed by decreasing fat mass through dietary intervention. Four-week-old C57BL/6J mice were assigned to 1 of 3 experimental diet groups: (1) the LL group was fed a control diet for 31 weeks, (2) the HH group was fed an HFD for 31 weeks, and (3) the HL group was fed HFD for 15 weeks then switched to the control diet for the remaining 16 weeks. The fat mass of the HL group decreased by 15% from the 14th to the 30th week. Serum 1,25(OH) 2 D level was significantly higher in the HH group than the LL group, whereas that of the HL group was intermediate to the 2 groups. Serum parathyroid hormone and renal 1-hydroxylase ( Cyp27b1 ) mRNA levels, which are known to stimulate renal 1,25(OH) 2 D production, were significantly higher in the HH group than the LL group. After losing fat mass, the HL group had significantly lower renal Cyp27b1 mRNA levels than the HH group. No differences were found in serum 25-hydroxyvitamin D levels and mRNA levels of hepatic 25-hydroxylases. In adipose tissue, mRNA levels of 25-hydroxylase and vitamin D receptor were elevated in parallel to the adiposity. In conclusion, serum 1,25(OH) 2 D levels were closely associated with body adiposity, and reducing fat mass by changing to a lower-fat diet can reverse this obesity-associated increase in circulating 1,25(OH) 2 D levels. [ABSTRACT FROM AUTHOR]

Vitamin D has an immunoregulatory effect on both innate and adaptive immunity. Contradictory results regarding vitamin D and natural killer (NK) cell functions have been reported with in vitro studies, but little is known about this in vivo. We investigated whether vitamin D levels (50, 1000 or 10,000 IU/kg of diet: DD, DC or DS) affect NK cell functions in mice fed a control or high-fat diet (10% or 45% kcal fat: CD or HFD) for 12 weeks. The splenic NK cell activity was significantly higher in the CD-DS group than the HFD-DS group, and the CD-DS group showed significantly higher NK cell activity compared with the CD-DD and CD-DC groups. However, no difference in NK cell activity was observed among the HFD groups fed different levels of vitamin D. The splenic population of NK cells was significantly higher in the CD-DS group than the HFD-DS group. There was no difference in the intracellular expression of IFN-γ and the surface expression of NKG2D and CD107a in NK cells by both dietary fat and vitamin D content. The splenic mRNA expression of Ifng and Ccl5 was significantly lower in the HFD groups compared with the CD groups, but there was no difference in the mRNA levels of Vdup1 and Vdr among the groups. Taken together, these results suggest that dietary vitamin D supplementation can modulate innate immunity by increasing NK activity in control mice but not in obese mice. This effect might be mediated through alternation of the splenic NK cell population. [ABSTRACT FROM AUTHOR]

Obesity is associated with the dysregulation of vitamin D metabolism and altered immune responses in bone marrow-derived dendritic cells (BMDCs). Vitamin D can affect the differentiation, maturation, and activation of dendritic cells (DCs) and regulate autophagy via vitamin D receptor signaling. Autophagy was shown to be involved in the functions of DCs. We investigated the effects of dietary vitamin D supplementation and in vitro 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on autophagy in BMDCs from control diet (CON)-fed lean and high-fat diet (HFD)-induced obese mice. C57BL/6 male mice were fed CON or HFD with 10% or 45% kcal fat, respectively, supplemented with 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS) for 12 weeks. BMDCs were generated by culturing bone marrow cells from the mice with 20 ng/mL rmGM-CSF and treated with 1 nM 1,25(OH)2D3. Maturation of BMDCs was induced by lipopolysaccharide (50 ng/mL) stimulation. Treatment with 1,25(OH)2D3 inhibited the expression of phenotypes related to DC function (MHC class Ⅱ, CD86, CD80) and production of IL-12p70 by BMDCs from control and obese mice, regardless of dietary vitamin D supplementation. LC3Ⅱ/Ⅰ and VPS34 protein levels increased, and p62 expression decreased, after 1,25(OH)2D3 treatment of the BMDCs in CON-vDC only. Vdr mRNA levels decreased following 1,25(OH)2D3 treatment of BMDCs in the HFD-vDC. In conclusion, autophagy flux was increased by 1,25(OH)2D3 treatment of the BMDCs in CON-vDC but not in the HFD-vDC group. This suggests that the decreased expression of Vdr following 1,25(OH)2D3 treatment might have affected autophagy flux in BMDCs from obese mice. [ABSTRACT FROM AUTHOR]