Vai trò có lợi của vitamin D trong béo phì: những cơ chế di truyền và tín hiệu tế bào có thể

Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S: Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest. 1985, 76: 370-373. 10.1172/JCI111971. Fung GJ, Steffen LM, Zhou X, Harnack L, Tang W, et al: Vitamin D intake is inversely related to risk of developing metabolic syndrome in African American and white men and women over 20 y: the coronary artery risk development in young adults study. Am J Clin Nutr. 2012, 96: 24-29. 10.3945/ajcn.112.036863. Robinson C, Chiang M, Thompson SN, Sondike SB: Occurrence of vitamin D deficiency in pediatric patients at high risk in West Virginia. South Med J. 2012, 105: 504-507. 10.1097/SMJ.0b013e3182675e8a. Tamer G, Mesci B, Tamer I, Kilic D, Arik S: Is vitamin D deficiency an independent risk factor for obesity and abdominal obesity in women?. Endokrynol Pol. 2012, 63: 196-201. Josefson JL, Feinglass J, Rademaker AW, Metzger BE, Zeiss DM, et al: Maternal obesity and vitamin D sufficiency Are associated with cord blood vitamin D insufficiency. J Clin Endocrinol Metab. 2012, Epub ahead of print Sulistyoningrum DC, Green TJ, Lear SA, Devlin AM: Ethnic-specific differences in vitamin D status is associated with adiposity. PLoS One. 2012, 7: e43159-10.1371/journal.pone.0043159. Jungert A, Roth HJ, Neuhäuser-Berthold M: Serum 25-hydroxyvitamin D3 and body composition in an elderly cohort from Germany: a cross-sectional study. Nutr Metab (Lond). 2012, 9: 42-10.1186/1743-7075-9-42. Lee SH, Kim SM, Park HS, Choi KM, Cho GJ, et al: Serum 25-hydroxyvitamin D levels, obesity and the metabolic syndrome among Korean children. Nutr Metab Cardiovasc Dis. 2012, Epub ahead of print Saliba W, Barnett-Griness O, Rennert G: The relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation. Osteoporos Int. 2012, Epub ahead of print 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). 2013, 37: 651-7. 10.1038/ijo.2012.112. Morris KL, Zemel MB: 1,25-Dihydroxyvitamin D3 modulation of adipocyte glucocorticoid function. Obes Res. 2005, 13: 670-677. 10.1038/oby.2005.75. Salehpour A, Hosseinpanah F, Shidfar F, Vafa M, Razaghi M, et al: A 12-week double-blind randomized clinical trial of vitamin D3 supplementation on body fat mass in healthy overweight and obese women. Nutr J. 2012, 11: 78-10.1186/1475-2891-11-78. Nagpal J, Pande JN, Bhartia A: A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med. 2009, 26: 19-27. 10.1111/j.1464-5491.2008.02636.x. Lương KVQ, Nguyễn LTH: Vitamin D and obesity. Medicinal Chemistry (OMICS). 2012, 2: 1- Sato M, Hiragun A: Demonstration of 1 alpha,25-dihydroxyvitamin D3 receptor-likemolecule in ST 13 and 3T3 L1 preadipocytes and its inhibitory effects on preadipocyte differentiation. J Cell Physiol. 1988, 135: 545-550. 10.1002/jcp.1041350326. Blumberg JM, Tzameli I, Astapova I, Lam FS, Flier JS, Hollenberg AN: Complex role of the vitamin D receptor and its ligand in adipogenesis in 3T3-L1 cells. J. Biol. Chem. 2006, 281: 11205-11213. 10.1074/jbc.M510343200. Fu M, Sun T, Bookout AL, Downes M, Yu RT, et al: A nuclear receptor atlas: 3T3-L1 adipogenesis. Mol Endocrinol. 2005, 19: 2437-2450. 10.1210/me.2004-0539. Imagawa M, Tsuchiya T, Nishihara T: Identification of inducible genes at the early stage of adipocyte differentiation of 3T3-L1 cells. Biochem Biophy Res Commun. 1999, 254: 299-305. 10.1006/bbrc.1998.9937. Lee S, Lee DK, Choi E, Lee JW: Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes. Mol Endocrinol. 2005, 19: 399-408. Guzey M, Jukic D, Arlotti J, Acquafondata M, Dhir R, Getzenberg RH: Increased apoptosis of periprostattic adipose tissue in VDR null mice. J Cell Biochem. 2004, 93: 133-141. 10.1002/jcb.20172. Zinzer GM, Welsh JE: Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. Carcinogenesis. 2004, 25: 2361-2372. 10.1093/carcin/bgh271. Wong KE, Szeto FL, Zhang W, Ye H, et al: Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins. Am J Physiol Endocrinol Metab. 2009, 296: E820-E828. 10.1152/ajpendo.90763.2008. 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, 150: 651-661. Weber K, Erben RG: Differences in triglyceride and cholesterol metabolism and resistance to obesity in male and female vitamin D receptor knockout mice. J Anim Physiol Anim Nutr (Berl). 2012, 10.1111/j.1439-0396.2012.01308.x. [Epub ahead of print] Wong KE, Kong J, Zhang W, Szeto FL, Ye H, et al: Targeted expression of human vitamin D receptor in adipocytes decreases energy expenditure and induces obesity in mice. J Biol Chem. 2011, 286: 33804-33810. 10.1074/jbc.M111.257568. Santos BR, Mascarenhas LP, Satler F, Boguszewski MC, Spritzer PM: Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants. BMC Pediatr. 2012, 12: 62-10.1186/1471-2431-12-62. Ye WZ, Reis AF, Dubois-Laforgue D, Bellanné-Chantelot C, et al: Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol. 2001, 145: 181-186. 10.1530/eje.0.1450181. Vasilopoulos Y, Sarafidou T, Kotsa K, Papadimitriou M, Goutzelas Y, et al: VDR TaqI is associated with obesity in the Greek population. Gene. 2013, 512: 237-239. 10.1016/j.gene.2012.10.044. Binh TQ, Nakahori Y, Hien VT, Khan NC, Lam NT, et al: Correlations between genetic variance and adiposity measures, and gene x gene interactions for obesity in postmenopausal Vietnamese women. J Genet. 2011, 90: 1-9. 10.1007/s12041-011-0028-3. Filus A, Trzmiel A, Kuliczkowska-Płaksej J, Tworowska U, Jedrzejuk D, et al: Relationship between vitamin D receptor BsmI and FokI polymorphisms and anthropometric and biochemical parameters describing metabolic syndrome. Aging Male. 2008, 11: 134-139. 10.1080/13685530802273426. Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, et al: Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007, 292: E740-E747. Kim SJ, Choi Y, Choi YH, Park T: Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice. J Nutr Biochem. 2012, 23: 113-122. 10.1016/j.jnutbio.2010.10.012. Vitseva OI, Tanriverdi K, Tchkonia TT, Kirkland JL, McDonnell ME, et al: Inducible Toll-like receptor and NF-kappaB regulatory pathway expression in human adipose tissue. Obesity (Silver Spring). 2008, 16: 932-937. 10.1038/oby.2008.25. Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME: Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring). 2008, 16: 1248-1255. 10.1038/oby.2008.210. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, et al: Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007, 56: 1986-1998. 10.2337/db06-1595. Suganami T, Mieda T, Itoh M, Shimoda Y, Kamei Y, Ogawa Y: Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun. 2007, 354: 45-49. 10.1016/j.bbrc.2006.12.190. Caricilli AM, Nascimento PH, Pauli JR, Tsukumo DM, Velloso LA, et al: Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet. J Endocrinol. 2008, 199: 399-406. 10.1677/JOE-08-0354. Jermendy A, Korner A, Kovacs M, Kaszas E, Balázsovics J, et al: Association between toll-like receptor polymorphisms and serum levels of tumor necrosis factor-alpha and its soluble receptors in obese children. Med Sci Monit. 2010, 16: CR180-CR185. Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, et al: Vitamin D deficiency in obese rats exacerbates NAFLD and increases hepatic resistin and toll-like receptor activation. Hepatol. 2012, 55: 1103-1111. 10.1002/hep.24737. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, et al: Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006, 36: 361-370. 10.1002/eji.200425995. Dickie L, Church L, Coulthard L, Mathews R, Emery P, McDermott M: Vitamin D3 downregulates intracellular toll-like receptor 9 expression and toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatol. 2010, 48: 1466-1471. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, et al: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006, 311: 1770-1773. 10.1126/science.1123933. Johnston CI: Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension. 1994, 23: 258-268. 10.1161/01.HYP.23.2.258. Karlsson C, Lindell K, Ottosson M, Sjöström L, Carlsson B, Carlsson LM: Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab. 1998, 83: 3925-3929. 10.1210/jc.83.11.3925. Engeli S, Gorzelniak K, Kreutz R, Runkel N, Distler A, Sharma AM: Co-expression of renin-angiotensin system genes in human adipose tissue. J Hypertens. 1999, 17: 555-560. 10.1097/00004872-199917040-00014. Fowler JD, Johnson ND, Haroldson TA, Brintnall JA, Herrera JE, et al: Regulated renin release from 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2009, 296: E1383-E1391. 10.1152/ajpendo.00025.2009. Achard V, Boullu-Ciocca S, Desbriere R, Nguyen G, Grino M: Renin receptor expression in human adipose tissue. Am J Physiol Regul Integr Comp Physiol. 2007, 292: R274-R282. Ho JT, Keogh JB, Bornstein SR, Ehrhart-Bornstein M, Lewis JG, et al: Moderate weight loss reduces renin and aldosterone but does not influence basal or stimulated pituitary-adrenal axis function. Horm Metab Res. 2007, 39: 694-699. 10.1055/s-2007-985354. Jones BH, Standridge MK, Moustaid N: Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells. Endocrinology. 1997, 138: 1512-1519. 10.1210/en.138.4.1512. Massiera F, Seydoux J, Geloen A, Quignard-Boulange A, Turban S, et al: Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity. Endocrinology. 2001, 142: 5220-5225. 10.1210/en.142.12.5220. Yvan-Charvet L, Even P, Bloch-Faure M, Guerre-Millo M, Moustaid-Moussa N, et al: Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance. Diabetes. 2005, 54: 991-999. 10.2337/diabetes.54.4.991. Iwai M, Tomono Y, Inaba S, Kanno H, Senba I, et al: AT2 receptor deficiency attenuates adipocyte differentiation and decreases adipocyte number in atherosclerotic mice. Am J Hypertens. 2009, 22: 784-791. 10.1038/ajh.2009.85. Matsushita K, Wu Y, Okamoto Y, Pratt RE, Dzau VJ: Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension. 2006, 48: 1095-1102. 10.1161/01.HYP.0000248211.82232.a7. Vaziri ND, Xu ZG, Shahkarami A, Huang KT, Rodríguez-Iturbe B, Natarajan R: Role of AT-1 receptor in regulation of vascular MCP-1, IL-6, PAI-1, MAP kinase, and matrix expressions in obesity. Kidney Int. 2005, 68: 2787-2793. 10.1111/j.1523-1755.2005.00750.x. Toblli JE, Muñoz MC, Cao G, Mella J, Pereyra L, Mastai R: ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring). 2008, 16: 770-776. 10.1038/oby.2007.114. Procopciuc LM, Sitar-Tăut A, Pop D, Sitar-Tăut DA, Olteanu I, Zdrenghea D: Renin angiotensin system polymorphisms in patients with metabolic syndrome (MetS). Eur J Intern Med. 2010, 21: 414-418. 10.1016/j.ejim.2010.06.001. Hamada T, Kotani K, Nagai N, Tsuzaki K, Sano Y, et al: Genetic polymorphisms of the renin-angiotensin system and obesity-related metabolic changes in response to low-energy diets in obese women. Nutrition. 2011, 27: 34-39. 10.1016/j.nut.2009.10.012. Mehri S, Mahjoub S, Hammami S, Zaroui A, Frih A, et al: Renin-angiotensin system polymorphisms in relation to hypertension status and obesity in a Tunisian population. Mol Biol Rep. 2012, 39: 4059-4065. 10.1007/s11033-011-1187-2. Strazzullo P, Iacone R, Iacoviello L, Russo O, Barba G, et al: Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti prospective heart study. Ann Intern Med. 2003, 138: 17-23. 10.7326/0003-4819-138-1-200301070-00007. Wacker MJ, Godard MP, McCabe EH, Donnelly JE, Kelly JK: Sex difference in the association of the angiotensin converting enzyme I/D polymorphism and body mass index. Med Sci Monit. 2008, 14: CR353-CR357. Kota SK, Kota SK, Jammula S, Meher LK, Panda S, et al: Renin-angiotensin system activity in vitamin D deficient, obese individuals with hypertension: An urban Indian study. Indian J Endocrinol Metab. 2011, 15 (Suppl 4): S395-S401. Tomaschitz A, Pilz S, Ritz E, Grammer T, Drechsler C, Boehm BO, März W: Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system: the Ludwigshafen risk and cardiovascular health (LURIC) study. Clin Chim Acta. 2010, 411: 1354-1360. 10.1016/j.cca.2010.05.037. Xiang W, Kong J, Chen S, Cao L, Qiao G, et al: Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Phys Endocrinol Met. 2005, 288: E125-E132. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D: Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008, 74: 170-179. 10.1038/ki.2008.101. Kong J, Qiao G, Zhang Z, Liu SQ, Li YC: Targeted vitamin D receptor expression in juxtaglomerular cells suppresses renin expression independent of parathyroid hormone and calcium. Kidney Int. 2008, 74: 1577-1581. 10.1038/ki.2008.452. Yuan W, Pan W, Kong J, Zheng W, Szeto F, et al: 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007, 282: 29821-29830. 10.1074/jbc.M705495200. Higiwara H, Furuhashi H, Nakaya K, Nakamura Y: Effects of vitamin D3 and related compounds on angiotensin converting activity of endothelial cells and on release of plasminogen activator from them. Chem Pharm Bull. 1988, 36: 4858-4864. 10.1248/cpb.36.4858. Vaidya A, Forman JP, Williams JS: Vitamin D and the vascular sensitivity to angiotensin II in obese Caucasians with hypertension. J Hum Hypertens. 2011, 25: 672-678. 10.1038/jhh.2010.110. Vaidya A, Sun B, Larson C, Forman JP, Williams JS: Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study. J Clin Endocrinol Metab. 2012, 97: 2456-2465. 10.1210/jc.2012-1156. Zechner R, Moser R, Newman TC, Fried SK, Breslow JL: Apolipoprotein E gene expression in mouse 3T3-L1 adipocytes and human adipose tissue and its regulation by differentiation and lipid content. J Biol Chem. 1991, 266: 10583-10588. Huang ZH, Reardon CA, Mazzone T: Endogenous ApoE expression modulates adipocyte triglyceride content and turnover. Diabetes. 2006, 55: 3394-3402. 10.2337/db06-0354. Rao P, Huang ZH, Mazzone T: Angiotensin II regulates adipocyte apolipoprotein E expression. J Clin Endocrinol Metab. 2007, 92: 4366-4372. 10.1210/jc.2007-1592. Huang ZH, Gu D, Mazzone T: Role of adipocyte-derived apoE in modulating adipocyte size, lipid metabolism, and gene expression in vivo. Am J Physiol Endocrinol Metab. 2009, 296: E1110-E1119. 10.1152/ajpendo.90964.2008. Carmel JF, Tarnus E, Cohn JS, Bourdon E, Davignon J, Bernier L: High expression of apolipoprotein E impairs lipid storage and promotes cell proliferation in human adipocytes. J Cell Biochem. 2009, 106: 608-617. 10.1002/jcb.22037. VanEck M, Herijgers N, Yates J, Pearce NJ, Hoogerbrugge PM, Berkel TJV: Bone marrow transplantation in apolipoprotein E-deficient mice. Effect of apoE gene dosage on serum lipid concentrations, betaVLDL catabolism, and atherosclerosis. Arterioscl Thromb Vasc Biol. 1997, 17: 3117-3126. 10.1161/01.ATV.17.11.3117. Atkinson RD, Coenen KR, Plummer MR, Gruen ML, Hasty AH: Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice. Am J Physiol Endocrinol Metab. 2008, 294: E284-E290. Kuhel DG, Konaniah ES, Basford JE, McVey C, Goodin CT, Chatterjee TK, Weintraub NL, Hui DY: Apolipoprotein E2 accentuates postprandial inflammation and diet-induced obesity to promote hyperinsulinemia in mice. Diabetes. 2012, Epub ahead of print Huang ZH, Maeda N, Mazzone T: Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis. J Lipid Res. 2011, 52: 1733-1741. 10.1194/jlr.M017160. Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, et al: APOE ϵ4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J. 2011, 25: 3262-3270. 10.1096/fj.11-180935. Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, et al: Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res. 1997, 12: 1438-1445. 10.1359/jbmr.1997.12.9.1438. Gerdes LU, Vestergaard P, Hermann AP, Mosekilde L: Regional and hormone-depenpent effects of apolipoprotein E genotype on changes in bone mineral in perimenopausal women. J Bone Miner Res. 2001, 16: 1906-1916. 10.1359/jbmr.2001.16.10.1906. Jouni ZE, McNamara DJ: Lipoprotein receptors of HL-60 macrophages. Effect of differentiation with tetramyristic phorbol acetate and 1,25-dihydroxyvitamin D3. Arterioscler Thromb. 1991, 11: 995-1006. 10.1161/01.ATV.11.4.995. Husain K, Suarez E, Isidro A, Ferder L: Effects of paricalcitol and enalapril on atherosclerotic injury in mouse aortas. Am J Nephrol. 2010, 32: 296-304. 10.1159/000319445. Becker LE, Koleganova N, Piecha G, Noronha IL, Zeier M, et al: Effects of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice. Am J Physiol Renal Physiol. 2011, 300: F772-F782. 10.1152/ajprenal.00042.2010. Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW: Vitamin D may not improve lipid levels: a serial clinical laboratory data study. Circulation. 2012, 126: 270-277. 10.1161/CIRCULATIONAHA.111.077875. Wang H, Xia N, Yang Y, Peng DQ: Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials. Lipids Health Dis. 2012, 11: 42-10.1186/1476-511X-11-42. Loebig M, Klement J, Schmoller A, Betz S, Heuck N, et al: Evidence for a relationship between VEGF and BMI independent of insulin sensitivity by glucose clamp procedure in a homogenous group healthy young men. PLoS One. 2010, 5: e12610-10.1371/journal.pone.0012610. Ledoux S, Queguiner I, Msika S, Calderari S, Rufat P, et al: Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity. Diabetes. 2008, 57: 3247-3257. 10.2337/db07-1812. Yamaguchi M, Matsumoto F, Bujo H, Shibasaki M, Takahashi K, et al: Revascularization determines volume retention and gene expression by fat grafts in mice. Exp Biol Med (Maywood). 2005, 230: 742-748. Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, et al: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A. 2002, 99: 10730-10735. 10.1073/pnas.162349799. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Yagui K, Saito Y: Roles of degree of fat deposition and its localization on VEGF expression in adipocytes. Am J Physiol Endocrinol Metab. 2005, 288: E1128-E1136. 10.1152/ajpendo.00003.2004. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y: Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia. 2003, 46: 1483-1488. 10.1007/s00125-003-1221-6. Kawamura T, Murakami K, Bujo H, Unoki H, Jiang M, et al: Matrix metalloproteinase-3 enhances the free fatty acids-induced VEGF expression in adipocytes through toll-like receptor 2. Exp Biol Med (Maywood). 2008, 233: 1213-1221. 10.3181/0801-RM-20. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, et al: Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature. 2010, 464: 917-921. 10.1038/nature08945. Tam J, Duda DG, Perentes JY, Quadri RS, et al: Blockade of VEGFR2 and not VEGFR1 can limit diet-induced fat tissue expansion: role of local versus bone marrow-derived endothelial cells. PLoS One. 2009, 4: e4974-10.1371/journal.pone.0004974. García de la Torre N, Rubio MA, Bordiú E, Cabrerizo L, Aparicio E, et al: Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab. 2008, 93: 4276-4281. 10.1210/jc.2007-1370. Belo VA, Souza-Costa DC, Luizon MR, Izidoro-Toledo TC, Lanna CM, et al: Vascular endothelial growth factor haplotypes associated with childhood obesity. DNA Cell Biol. 2011, 30: 709-714. 10.1089/dna.2011.1260. Mantell D, Owens P, Bundred N, Mawer E, Canfield A: 1α,25-dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. Circ Res. 2000, 87: 214-220. 10.1161/01.RES.87.3.214. Gruber H, Hoelscher G, Ingram J, Chow Y, Loffler B, Hanley E: 1α,25-dihydroxyvitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine. 2008, 33: 755-765. 10.1097/BRS.0b013e3181695d59. Albert D, Scheef E, Wang S, Mehraein F, Darjatmoko S, Sorenson C, Sheibani N: Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci. 2007, 48: 2327-2334. 10.1167/iovs.06-1210. Nakagawa K, Sasaki Y, Kato S, Kubodera N, Okano T: 22-Oxa-1α,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis. 2005, 26: 1044-1054. 10.1093/carcin/bgi049. Ben-Shoshan M, Amir S, Dang D, Dang L, Weisman Y, Mabjeesh N: 1α,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth pathway in human cancer cells. Mol Cancer Ther. 2007, 6: 1433-1439. 10.1158/1535-7163.MCT-06-0677. Kisker O, Onizuka S, Becker CM, Fannon M, Flynn E, et al: Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia. 2003, 5: 32-40. Kalkunte S, Brard L, Granai C, Swamy N: Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf. Angiogenesis. 2005, 8: 349-360. Krishnakumar R, Kraus WL: The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell. 2010, 39: 8-24. 10.1016/j.molcel.2010.06.017. Erener S, Hesse M, Kostadinova R, Hottiger MO: Poly(ADP-ribose)polymerase-1 (PARP1) controls adipogenic gene expression and adipocyte function. Mol Endocrinol. 2012, 26: 79-86. 10.1210/me.2011-1163. Devalaraja-Narashimha K, Padanilam BJ: PARP1 deficiency exacerbates diet-induced obesity in mice. J Endocrinol. 2010, 205: 243-252. 10.1677/JOE-09-0402. Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, et al: Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev. 1995, 9: 509-520. 10.1101/gad.9.5.509. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, et al: The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012, 15: 838-847. 10.1016/j.cmet.2012.04.022. Bai P, Canto C, Oudart H, Brunyánszki A, Cen Y, et al: PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism. 2011, 13- de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, et al: Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A. 1997, 94: 7303-7307. 10.1073/pnas.94.14.7303. Bai P, Houten SM, Huber A, Schreiber V, Watanabe M, et al: Poly(ADP-ribose) polymerase-2 [corrected] controls adipocyte differentiation and adipose tissue function through the regulation of the activity of the retinoid X receptor/peroxisome proliferator-activated receptor-gamma [corrected] heterodimer. J Biol Chem. 2007, 282: 37738-37746. 10.1074/jbc.M701021200. Bai P, Canto C, Brunyánszki A, Huber A, Szántó M, et al: PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab. 2011, 13: 450-460. 10.1016/j.cmet.2011.03.013. Yeh TY, Beiswenger KK, Li P, Bolin KE, Lee RM, et al: Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice. Diabetes. 2009, 58: 2476-2485. 10.2337/db08-1781. Bhatia M, Kirkland JB, Mecking-Gill KA: Modulation of poly(ADP-ribose) polymerase during neurophilic and monocytic differentiation of promyelocytic (NB4) and myelocytic (HL-60) leakaemia cells. Biochemical Journal. 1995, 308: 131-137. Mabley JG, Wallace R, Pacher P, Murphy K, Szab C: Inhibition of poly(adenosine diphosphate-ribose) polymerase by the active form of vitamin D. International Journal of Molecular Medicine. 2007, 9 (6): 947-952. Shen M, Yen A: Nicotinamide cooperates with retinoic acid and 1,25-dihydroxyvitamin D3 to regulate cell differentiation and cell cycle arrest of human myeloblastic leukemia cells. Oncology. 2009, 76: 91-100. 10.1159/000188664. Moore M, Piazza A, Nolan Y, Lynch MA: Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age-related changes in rat hippocampus. Synapse. 2007, 61: 851-861. 10.1002/syn.20433. Bouloumié A, Sengenès C, Portolan G, et al: Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes. 2001, 50: 2080-2086. 10.2337/diabetes.50.9.2080. Miksztowicz V, Siseles N, Machulsky NF, Schreier L, Berg G: Increase in MMP-2 activity in overweight and obese women is associated with menopausal status. Climacteric. 2012, 15: 602-606. 10.3109/13697137.2012.667174. Laimer M, Kaser S, Kranebitte M, Sandhofer A, Muhlmann G, et al: Effect of pronounced weight loss on the nontraditional cardiovascular risk marker matrix metalloproteinase-9 in middle-aged morbidly obese women. Int J Obes. 2005, 29: 498-501. Garvin P, Nilsson L, Carstensen J, Jonasson L, Kristenson M: Circulating matrix metalloproteinase-9 is associated with cardiovascular risk factors in a middle-aged normal population. PLoS One. 2008, 3: e1774-10.1371/journal.pone.0001774. Głowińska-Olszewska B, Urban M: Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. Metabolism. 2007, 56: 799-805. 10.1016/j.metabol.2007.01.011. Belo VA, Souza-Costa DC, Lana CM, Caputo FL, Marcaccini AM, et al: Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents. Clin Biochem. 2009, 42: 984-990. 10.1016/j.clinbiochem.2009.03.025. Morgan AR, Han DY, Thompson JM, Mitchell EA, Ferguson LR: Analysis of MMP2 promoter polymorphisms in childhood obesity. BMC Res Notes. 2011, 4: 253-10.1186/1756-0500-4-253. Andrade VL, Fernandes KS, Bosco AA, Tanus-Santos JE, Sandrim VC: Functional polymorphism located in MMP-9 gene promoter is strongly associated with obesity. DNA Cell Biol. 2012, 31: 1054-1057. 10.1089/dna.2011.1526. Belo VA, Souza-Costa DC, Luizon MR, Lanna CM, Carneiro PC, et al: Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children. Int J Obes (Lond). 2012, 36: 69-75. 10.1038/ijo.2011.169. Sundar I, Hwang J, Wu S, Sun J, Rahman I: Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinase and lymphoid aggregates formation. Biochem Biophys Res Commun. 2011, 406: 127-133. 10.1016/j.bbrc.2011.02.011. Timms P, Mannan N, Hitman G: Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?. Q J Med. 2002, 95: 787-796. 10.1093/qjmed/95.12.787. Dean DD, Schwartz Z, Schmitz J, Muniz OE, Lu Y, et al: Vitamin D regulation of metalloproteinase activity in matrix vesicles. Connect Tissue Res. 1996, 35: 331-336. 10.3109/03008209609029208. Bahar-shany K, Ravid A, Koren R: Upregulation of MMP-production by TNFalpha in keratinocytes and its attenuation by vitamin D. J Cell Physiol. 2010, 222: 729-737. Lacraz S, Dayer J, Nicod L, Welgus H: 1,25-dihydroxyvitamin D3 dissociates production of interstitial collagenase and 92-kDa gelatinase in human mononuclear phagocytes. J Biol Chem. 1994, 269: 6485-6490. Hipskind RA, Bilbe G: MAP kinase signaling cascades and gene expression in osteoblasts. Front Biosci. 1998, 3: d804-d816. Aouadi M, Jager J, Laurent K, Gonzalez T, Cormont M, et al: p38MAP Kinase activity is required for human primary adipocyte differentiation. FEBS Lett. 2007, 581: 5591-5596. 10.1016/j.febslet.2007.10.064. Roth RJ, Le AM, Zhang L, Kahn M, Samuel VT, et al: MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. J Clin Invest. 2009, 119: 3817-3829. 10.1172/JCI39054. Wu JJ, Roth RJ, Anderson EJ, Hong EG, Lee MK, et al: Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab. 2006, 4: 61-73. 10.1016/j.cmet.2006.05.010. Ito A, Suganami T, Miyamoto Y, Yoshimasa Y, Takeya M, et al: Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy. J Biol Chem. 2007, 282: 25445-25452. 10.1074/jbc.M701549200. Katiyar SK, Meeran SM: Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-kappaB signaling. Free Radic Biol Med. 2007, 42: 299-310. 10.1016/j.freeradbiomed.2006.10.049. Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binétruy B, Bost F: Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes. 2006, 55: 281-289. 10.2337/diabetes.55.02.06.db05-0963. Rask-Andersen M, Jacobsson JA, Moschonis G, Ek AE, Chrousos GP, et al: The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children. BMC Med Genet. 2012, 13: 36- Sun C, Qi R, Wang L, Yan J, Wang Y: p38 MAPK regulates calcium signal-mediated lipid accumulation through changing VDR expression in primary preadipocytes of mice. Mol Biol Rep. 2012, 39: 3179-3184. 10.1007/s11033-011-1084-8. Ravid A, Rubinstein E, Gamady A, Rotem C, Liberman UA, Koren R: Vitamin D inhibits the activation of stress-activated protein kinases by physiological and environmental stresses in keratinocytes. J Endocrinol. 2002, 173: 525-532. 10.1677/joe.0.1730525. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, et al: Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012, 188: 2127-2135. 10.4049/jimmunol.1102412. Tetich M, Kutner A, Leskiewicz M, Budziszewska B, Lasoń W: Neuroprotective effects of (24R)-1,24-dihydroxycholecalciferol in human neuroblastoma SH-SY5Y cell line. J Steroid Biochem Mol Biol. 2004, 89–90: 365-370. Liakhovich AV, Aksenov NL, Tuokhima P, Mikhel’son VM: Long-term action of vitamin D suppresses the estradiol-induced activity of erk-1 MAPK and proliferation of MCF-7 and LNCaP cancer cells. Tsitologiia. 2000, 42: 977-982. Article in Russian Jiang F, Lim HK, Morris MJ, Prior L, Velkoska E, et al: Systemic upregulation of NADPH oxidase in diet-induced obesity in rats. Redox Rep. 2011, 16: 223-229. 10.1179/174329211X13049558293713. Silver AE, Beske SD, Christou DD, Donato AJ, Moreau KL, et al: Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress. Circulation. 2007, 115: 627-637. 10.1161/CIRCULATIONAHA.106.657486. Mouche S, Mkaddem SB, Wang W, Katic M, Tseng YH, et al: Reduced expression of the NADPH oxidase NOX4 is a hallmark of adipocyte differentiation. Biochim Biophys Acta. 2007, 1773: 1015-1027. 10.1016/j.bbamcr.2007.03.003. Schröder K, Wandzioch K, Helmcke I, Brandes RP: Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler Thromb Vasc Biol. 2009, 29: 239-245. 10.1161/ATVBAHA.108.174219. Li Y, Mouche S, Sajic T, Veyrat-Durebex C, Supale R, et al: Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity. Int J Obes (Lond). 2012, 36: 1503-1513. 10.1038/ijo.2011.279. Kanda Y, Hinata T, Kang SW, Watanabe Y: Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci. 2011, 89: 250-258. 10.1016/j.lfs.2011.06.007. Yuan H, Zhang X, Huang X, Lu Y, Tang W, et al: NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS One. 2010, 5: e15726-10.1371/journal.pone.0015726. Hashizume K, Suzuki S, Ichikawa K, Takeda T, Kobayashi M: Effect of active vitamin D3 on the levels of NADPH-dependent cytosolic 3,5,3′-triiodo-L-thyronine-binding protein. Biochem Biophys Res Commun. 1991, 177: 388-394. 10.1016/0006-291X(91)91995-O. Stio M, Lunghi B, Iantomasi T, Vincenzini MT, Treves C: Effect of vitamin D deficiency and 1,25-dihydroxyvitamin D3 on rat heart metabolism. J Mol Cell Cardiol. 1994, 26: 1421-1428. 10.1006/jmcc.1994.1161. Bachelet M, Bader C, Merlot AM, Laborde K, Snarska J, Ulmann A: Cellular utilization of cytosolic NADPH in kidney and liver cells from rats fed a normal or a vitamin D-deficient diet. Cell Biochem Funct. 1983, 1: 25-29. 10.1002/cbf.290010105. Husain K, Ferder L, Mizobuchi M, Finch J, Slatopolsky E: Combination therapy with paricalcitol and enalapril ameliorates cardiac oxidative injury in uremic rats. Am J Nephrol. 2009, 29: 465-472. 10.1159/000178251. Fujitani Y, Aritake K, Kanaoka Y, Goto T, Takahashi N, et al: Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2 in vivo. FEBS J. 2010, 277: 1410-1419. 10.1111/j.1742-4658.2010.07565.x. Ghoshal S, Trivedi DB, Graf GA, Loftin CD: Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice. J Biol Chem. 2011, 286: 889-898. 10.1074/jbc.M110.139139. Casimir DA, Miller CW, Ntambi JM: Preadipocyte differentiation blocked by prostaglandin stimulation of prostanoid FP2 receptor in murine 3T3-L1 cells. Differentiation. 1996, 60: 203-210. 10.1046/j.1432-0436.1996.6040203.x. Serrero G, Lepak NM: Prostaglandin F2α a receptor (FP receptor) agonists are potent adipose differentiation inhibitors for primary culture of adipocyte precursors in defined medium. Biochem Biophys Res Commun. 1997, 233: 200-202. 10.1006/bbrc.1997.6433. Fujimori K, Ueno T, Amano F: Prostaglandin F2α suppresses early phase of adipogenesis, but is not associated with osteoblastogenesis in mouse mesenchymal stem cells. Prostaglandins Other Lipid Mediat. 2010, 93: 52-59. 10.1016/j.prostaglandins.2010.06.005. Henkel J, Frede K, Schanze N, Vogel H, Schürmann A, et al: Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis. Lab Invest. 2012, 92: 1597-1606. 10.1038/labinvest.2012.128. Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, et al: Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2012, 2: 356-365. 10.1158/2159-8290.CD-11-0241. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D: Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Research. 2005, 65: 7917-7925. Aparna R, Subhashini J, Roy KR, Reddy GS, Robinson M, et al: Selective inhibition of cyclooxygenase-2 (COX-2) by 1 α,25-dihydroxy- 16-ene-23-yne-vitamin D3, a less calcemic vitamin D analog. J Cell Biochem. 2008, 104: 1832-1842. 10.1002/jcb.21749. Kotani K, Taniguchi N: The association between reactive oxygen metabolites and metabolic syndrome in asymptomatic Japanese men. J Clin Med Res. 2011, 3: 247-251. Freeman LR, Zhang L, Nair A, Dasuri K, Francis J, Fernandez-Kim SO, Bruce-Keller AJ, Keller JN: Obesity increases cerebrocortical reactive oxygen species and impairs brain function. Free Radic Biol Med. 2013, 56: 226-33. de Farias JM, Bom KF, Tromm CB, Luciano TF, Marques SO, et al: Effect of physical training on the adipose tissue of diet-induced obesity mice: interaction between reactive oxygen species and lipolysis. Horm Metab Res. 2012, Epub ahead of print Bondia-Pons I, Ryan L, Martinez JA: Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem. 2012, 68: 701-711. 10.1007/s13105-012-0154-2. Codoñer-Franch P, Valls-Bellés V, Arilla-Codoñer A, Alonso-Iglesias E: Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress. Transl Res. 2011, 158: 369-384. 10.1016/j.trsl.2011.08.004. Boden MJ, Brandon AE, Tid-Ang JD, Preston E, Wilks D, et al: Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2012, 303: E798-E805. 10.1152/ajpendo.00577.2011. Hey-Mogensen M, Jeppesen J, Madsen K, Kiens B, Franch J: Obesity augments the age-induced increase in mitochondrial capacity for H2O2 release in Zucker fatty rats. Acta Physiol (Oxf). 2012, 204: 354-361. 10.1111/j.1748-1716.2011.02347.x. Amer MA, Ghattas MH, Abo-Elmatty DM, Abou-El-Ela SH: Evaluation of glutathione S-transferase P1 genetic variants affecting type-2 diabetes susceptibility and glycemic control. Arch Med Sci. 2012, 8: 631-636. Goyal R, Singhai M, Faizy AF: Glutathione peroxidase activity in obese and nonobese diabetic patients and role of hyperglycemia in oxidative stress. J Midlife Health. 2011, 2: 72-76. Pastore A, Ciampalini P, Tozzi G, Pecorelli L, Passarelli C, et al: All glutathione forms are depleted in blood of obese and type 1 diabetic children. Pediatr Diabetes. 2012, 13: 272-277. 10.1111/j.1399-5448.2011.00806.x. Gluck WL, Weinberg JB: 1 alpha,25 Dihydroxyvitamin D3 and mononuclear phagocytes: enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis. J Leukoc Biol. 1987, 42: 498-503. Cohen MS, Mesler DE, Snipes RG, Gray TK: 1,25-Dihydroxyvitamin D3 activates secretion of hydrogen peroxide by human monocytes. J Immunol. 1986, 136: 1049-1053. Levy R, Malech HL: Effect of 1,25-dihydroxyvitamin D3, lipopolysaccharide, or lipoteichoic acid on the expression of NADPH oxidase components in cultured human monocytes. J Immunol. 1991, 147: 3066-3071. Bao BY, Ting HJ, Hsu JW, Lee YF: Protective role of 1α, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer. 2008, 122: 2699-2706. 10.1002/ijc.23460. Somjen D, Katzburg S, Grafi-Cohen M, Knoll E, Sharon O, Posner GH: Vitamin D metabolites and analogs induce lipoxygenase mRNA expression and activity as well as reactive oxygen species (ROS) production in human bone cell line. J Steroid Biochem Mol Biol. 2011, 123: 85-89. 10.1016/j.jsbmb.2010.11.010. Garcion E, Sindji L, Leblondel G, Brachet P, Darcy F: 1,25-dihydroxyvitamin D3 regulates the synthesis of γ-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem. 1999, 73: 859-866. Martins MA, Catta-Preta M, Mandarim-de-Lacerda CA, Aguila MB, Brunini TC, Mendes-Ribeiro AC: High fat diets modulate nitric oxide biosynthesis and antioxidant defence in red blood cells from C57BL/6 mice. Arch Biochem Biophys. 2010, 499: 56-61. 10.1016/j.abb.2010.04.025. Jebelovszki E, Kiraly C, Erdei N, Feher A, Pasztor ET, et al: High-fat diet-induced obesity leads to increased NO sensitivity of rat coronary arterioles: role of soluble guanylate cyclase activation. Am J Physiol Heart Circ Physiol. 2008, 294: H2558-H2564. 10.1152/ajpheart.01198.2007. Vignini A, Nanetti L, Moroni C, Testa R, Sirolla C, et al: Platelet nitric oxide production and IR: relation with obesity and hypertriglyceridemia. Nutr Metab Cardiovasc Dis. 2008, 18: 553-558. 10.1016/j.numecd.2007.08.001. Tsuchiya K, Sakai H, Suzuki N, Iwashima F, Yoshimoto T, et al: Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice. Endocrinology. 2007, 148: 4548-4556. 10.1210/en.2006-1371. Cook S, Hugli O, Egli M, Menard B, Thalmann S, et al: Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes. 2004, 53: 2067-2072. 10.2337/diabetes.53.8.2067. Perreault M, Marette A: Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med. 2001, 7: 1138-1143. 10.1038/nm1001-1138. Chang JM, Kuo MC, Kuo HT, Hwang SJ, Tsai JC, et al: 1-α,25-Dihydroxyvitamin D3 regulates inducible nitric oxide synthase messenger RNA expression and nitric oxide release in macrophage-like RAW264.7 cells. J Lab Clin Med. 2004, 143: 14-22. 10.1016/j.lab.2003.08.002. Garcion E, Nataf S, Berod A, Darcy F, Brachet P: 1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Brain Res Mol Brain Res. 1997, 45: 255-267. 10.1016/S0169-328X(96)00260-4. Equils O, Naiki Y, Shapiro AM, Michelsen K, Lu D, et al: 1,25-Dihydroxyvitamin D3 inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol. 2006, 143: 58-64. 10.1111/j.1365-2249.2005.02961.x. Zittermann A, Frisch S, Berthold HK, Götting C, Kuhn J, et al: Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009, 89: 1321-1327. 10.3945/ajcn.2008.27004. Sneve M, Figenschau Y, Jorde R: Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol. 2008, 159: 675-684. 10.1530/EJE-08-0339. Boon N, Hul GB, Sicard A, Kole E, Van Den Berg ER, et al: The effects of increasing serum calcitriol on energy and fat metabolism and gene expression. Obesity (Silver Spring). 2006, 14: 1739-1746. 10.1038/oby.2006.200. Jorde R, Sneve M, Torjesen P, Figenschau Y: No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med. 2010, 267: 462-472. 10.1111/j.1365-2796.2009.02181.x. Lumb GA, Mawer EB, Stanbury SW: The apparent vitamin D resistance of chronic renal failure: a study of the physiology of vitamin D in man. Am J Med. 1971, 50: 421-444. 10.1016/0002-9343(71)90332-9. Mawer EB, Backhouse J, Holman CA, Lumb GA, Stanbury SW: The distribution and storage of vitamin D and its metabolites in human tissues. Clin Sci. 1972, 43: 413-431. Jorde R, Sneve M, Torjesen PA, Figenschau Y, Gøransson LG, Omdal R: No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects. Cytokine. 2010, 50: 175-180. 10.1016/j.cyto.2009.12.006. Sun X, Zemel MB: Calcium and 1,25-dihydroxyvitamin D3 regulation of adipokine expression. Obesity (Silver Spring). 2007, 15: 340-348. 10.1038/oby.2007.540. 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). 2013, 37 (3): 357-65. 10.1038/ijo.2012.53. Marcotorchino J, Gouranton E, Romier B, Tourniaire F, Astier J, et al: Vitamin D reduces the inflammatory response and restores glucose uptake in adipocytes. Mol Nutr Food Res. 2012, 56: 1771-1782. 10.1002/mnfr.201200383. McCarthy MF, Thomas CA: PTH excess may promote weight gain by impeding catecholamine-induced lipolysis-implications for the impact of calcium, vitamin D, and alcohol on body weight. Medical Hypotheses. 2003, 61: 535-542. 10.1016/S0306-9877(03)00227-5. Bell NH, Shaw S, Turner RT: Evidence that calcium modulates circulating 25-hydroxyvitamin D in man. J Bone Miner Res. 1987, 2: 211-214. Luong KV, Nguyen LT: Coexisting hyperthyroidism and primary hyperparathyroidism with vitamin D-deficient osteomalacia in a Vietnamese immigrant. Endocr Pract. 1996, 2: 250-254. 10.4158/EP.2.4.250.