Abstract
Background/aim
Obesity is characterized by a low-grade inflammation in white adipose tissue (WAT), which promotes insulin resistance. Low serum levels of 1α,25-dihydroxycholecalciferol (DHCC) associate with insulin resistance and higher body mass index although it is unclear whether vitamin D supplementation improves insulin sensitivity. We investigated the effects of DHCC on adipokine gene expression and secretion in adipocytes focusing on two key factors with pro-inflammatory [monocyte chemoattractant protein-1 (MCP-1/CCL2)] and anti-inflammatory [adiponectin (ADIPOQ)] effects.
Methods
Pre-adipocytes were isolated from human subcutaneous WAT and cultured until full differentiation. Differentiated adipocytes were either pre-treated with DHCC (10−7 M) and subsequently incubated with tumor necrosis factor-α (TNFα, 100 ng/mL) or concomitantly incubated with TNFα/DHCC. MCP1 and adiponectin mRNA expression was measured by RT–PCR and protein release by ELISA.
Results
DHCC was not toxic and did not affect adipocyte morphology or the mRNA levels of adipocyte-specific genes. TNFα induced a significant increase in CCL2 mRNA and protein secretion, while DHCC alone reduced CCL2 mRNA expression (~25%, p < 0.05). DHCC attenuated TNFα-induced CCL2 mRNA expression in both pre-incubation (~15%, p < 0.05) and concomitant (~60%, p < 0.01) treatments. TNFα reduced ADIPOQ mRNA (~80%) and secretion (~35%). DHCC alone decreased adiponectin secretion to a similar degree (~35%, p < 0.05). Concomitant treatment with DHCC/TNFα for 48 h had an additive effect, resulting in a pronounced reduction in adiponectin secretion (~70%).
Conclusions
DHCC attenuates MCP-1 and adiponectin production in human adipocytes, thereby reducing the expression of both pro- and anti-inflammatory factors. These effects may explain the difficulties so far in determining the role of DHCC in insulin sensitivity and obesity in humans.
Similar content being viewed by others
References
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95(5):2409–2415
Lofgren P, van Harmelen V, Reynisdottir S, Naslund E, Ryden M, Rossner S, Arner P (2000) Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes 49(5):688–692
Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Arner P (2002) Mapping of early signaling events in tumor necrosis factor-alpha-mediated lipolysis in human fat cells. J Biol Chem 277(2):1085–1091
Prins JB, Niesler CU, Winterford CM, Bright NA, Siddle K, O’Rahilly S, Walker NI, Cameron DP (1997) Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes 46(12):1939–1944
Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF (2002) Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3–L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51(5):1319–1336
Wang B, Trayhurn P (2006) Acute and prolonged effects of TNF-alpha on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflugers Arch 452(4):418–427
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116(6):1494–1505
Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, Kwon BS, Erickson KL, Yu R (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30(9):1347–1355
Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100(12):7265–7270
Trujillo ME, Scherer PE (2005) Adiponectin—journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 257(2):167–175
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86(5):1930–1935
Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52(7):1779–1785
Wang B, Jenkins JR, Trayhurn P (2005) Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-alpha. Am J Physiol Endocrinol Metab 288(4):E731–E740
Trayhurn P, Wang B, Wood IS (2008) Hypoxia and the endocrine and signalling role of white adipose tissue. Arch Physiol Biochem 114(4):267–276
Chiu KC, Chu A, Go VL, Saad MF (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79(5):820–825
Bischof MG, Heinze G, Vierhapper H (2006) Vitamin D status and its relation to age and body mass index. Horm Res 66(5):211–215
Zemel MB, Sun X (2008) Calcitriol and energy metabolism. Nutr Rev 66(10 Suppl 2):S139–S146
Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2001) 1alpha, 25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action. Faseb J 15(14):2751–2753
Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2002) 1alpha, 25-dihydroxyvitamin D3 inhibits uncoupling protein 2 expression in human adipocytes. Faseb J 16(13):1808–1810
Carlberg C, Seuter S (2009) A genomic perspective on vitamin D signaling. Anticancer Res 29(9):3485–3493
Sun X, Zemel MB (2007) 1Alpha, 25-dihydroxyvitamin D3 modulation of adipocyte reactive oxygen species production. Obesity (Silver Spring) 15(8):1944–1953
Zhang Z, Yuan W, Sun L, Szeto FL, Wong KE, Li X, Kong J, Li YC (2007) 1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int 72(2):193–201. doi:10.1038/sj.ki.5002296
Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C (2007) Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract 77(1):47–57
Chen Y, Kong J, Sun T, Li G, Szeto FL, Liu W, Deb DK, Wang Y, Zhao Q, Thadhani R, Li YC (2011) 1,25-Dihydroxyvitamin D suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-kappaB activation. Arch Biochem Biophys 507(2):241–247
van Harmelen V, Skurk T, Hauner H (2005) Primary culture and differentiation of human adipocyte precursor cells. Methods Mol Med 107:125–135. doi:1-59259-861-7:125
Dicker A, Astrom G, Sjolin E, Hauner H, Arner P, van Harmelen V (2007) The influence of preadipocyte differentiation capacity on lipolysis in human mature adipocytes. Horm Metab Res 39(4):282–287
Dicker A, Kaaman M, van Harmelen V, Astrom G, Blanc KL, Ryden M (2005) Differential function of the alpha2A-adrenoceptor and Phosphodiesterase-3B in human adipocytes of different origin. Int J Obes (Lond) 29(12):1413–1421. doi:10.1038/sj.ijo.0803042
Mairal A, Langin D, Arner P, Hoffstedt J (2006) Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia 49(7):1629–1636. doi:10.1007/s00125-006-0272-x
Pettersson AT, Mejhert N, Jernas M, Carlsson LM, Dahlman I, Laurencikiene J, Arner P, Ryden M Twist1 in human white adipose tissue and obesity. J Clin Endocrinol Metab 96(1):133–141. doi:10.1210/jc.2010-0929
Sun X, Morris KL, Zemel MB (2008) Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study. J Nutrigenet Nutrigenomics 1(1–2):30–48
Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455(3):479–492
Wood IS, Wang B, Lorente-Cebrian S, Trayhurn P (2007) Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-d-glucose uptake in human adipocytes. Biochem Biophys Res Commun 361(2):468–473. doi:10.1016/j.bbrc.2007.07.032
Sun X, Zemel MB (2007) Calcium and 1,25-dihydroxyvitamin D3 regulation of adipokine expression. Obesity (Silver Spring) 15(2):340–348
Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102(11):1296–1301
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7(8):941–946
Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE (1996) Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 10(11):1457–1466
Kruger S, Kreft B (2001) 1,25-dihydroxyvitamin D3 differentially regulates IL-1alpha-stimulated IL-8 and MCP-1 mRNA expression and chemokine secretion by human primary proximal tubular epithelial cells. Exp Nephrol 9(3):223–228
Zehnder D, Quinkler M, Eardley KS, Bland R, Lepenies J, Hughes SV, Raymond NT, Howie AJ, Cockwell P, Stewart PM, Hewison M (2008) Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation. Kidney Int 74(10):1343–1353. doi:10.1038/ki.2008.453
Sun X, Zemel MB (2008) Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk. J Nutr Biochem 19(6):392–399
Ailhaud G (1997) Molecular mechanisms of adipocyte differentiation. J Endocrinol 155(2):201–202
Sun X, Zemel MB (2004) Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB J 18(12):1430–1432. doi:10.1096/fj.04-1971fje
Mahajan A, Stahl CH (2009) Dihydroxy-cholecalciferol stimulates adipocytic differentiation of porcine mesenchymal stem cells. J Nutr Biochem 20(7):512–520
Alvarez JA, Ashraf A (2010) Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol 351–385. doi:10.1155/2010/351385
Acknowledgments
This work has been supported by Nordic Centre of Excellence on “Systems biology in controlled dietary interventions and cohort studies, SYSDIET (No. 070014)”. MR, PA, and ID are supported by grants from the Swedish Research Council. MR and PA are also supported by grants from the NovoNordisk Foundation and the Swedish Diabetes Fund.
Conflict of interest
All the authors have read and approved submission of the manuscript and declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
S. Lorente-Cebrián and A. Eriksson contributed equally to this work.
Rights and permissions
About this article
Cite this article
Lorente-Cebrián, S., Eriksson, A., Dunlop, T. et al. Differential effects of 1α,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes. Eur J Nutr 51, 335–342 (2012). https://doi.org/10.1007/s00394-011-0218-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00394-011-0218-z