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Effect of cinacalcet-mediated parathyroid hormone reduction on vitamin D metabolism in high-fat diet-induced obese mice

  • Tae Yeon, Kim (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Chan Yoon, Park (Department of Food and Nutrition, College of Health Science, The University of Suwon) ;
  • Sung Nim, Han (Department of Food and Nutrition, College of Human Ecology, Seoul National University)
  • Received : 2022.12.10
  • Accepted : 2023.02.01
  • Published : 2023.02.28

Abstract

Purpose: Obesity is associated with alterations in vitamin D metabolism and elevation of parathyroid hormone (PTH). Increased PTH level in obesity is likely one of the factors contributing to the dysregulation of vitamin D metabolism. We investigated the effects of lowering the PTH level in high-fat diet-induced obese mice on vitamin D metabolism. Methods: Five-week-old male C57BL/6N mice were fed either with control (10% energy as fat) or high-fat (60% energy as fat) diets ad libitum for 12 weeks, and vehicle or cinacalcet HCl (30 ㎍/g body weight) was gavaged daily during the final week of the experiment. The following groups were studied: CON (control diet + vehicle), HFD (high-fat diet + vehicle), and HFD-CIN (high-fat diet + cinacalcet HCl). PTH, 1,25-dihydroxyvitamin D (1,25[OH]2D), 25-hydroxyvitamin D (25[OH]D), calcium, and phosphate levels in circulation, and the expression of genes related to vitamin D metabolism in the liver and kidneys were determined. Results: Renal 1α-hydroxylase expression in the HFD group was higher than that in the CON group despite the lack of a difference in the PTH levels between the 2 groups. The plasma PTH level in the HFD-CIN group was 60% lower than that in the HFD group (p < 0.05). In parallel, the HFD-CIN group had lower adipose tissue amount (9% lower), renal 1α-hydroxylase expression (48% lower), and plasma 1,25(OH)2D concentration (38% lower) than the HFD group. Conclusion: Lowering the PTH levels in high-fat diet-induced obese mice recovered the expression of renal 1α-hydroxylase and might be associated with lower amounts of white adipose tissue.

Keywords

Acknowledgement

This work was supported by the National Research Foundation (NRF) of Korea (NRF-2015R1D1A1A01059679 and NRF2021R1A2C2012013).

References

  1. Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, et al. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab 2004; 89(3): 1196-1199. https://doi.org/10.1210/jc.2003-031398
  2. Shirazi L, Almquist M, Malm J, Wirfalt E, Manjer J. Determinants of serum levels of vitamin D: a study of life-style, menopausal status, dietary intake, serum calcium, and PTH. BMC Womens Health 2013; 13(1): 33.
  3. Liel Y, Ulmer E, Shary J, Hollis BW, Bell NH. Low circulating vitamin D in obesity. Calcif Tissue Int 1988; 43(4): 199-201. https://doi.org/10.1007/BF02555135
  4. Park JM, Park CY, Han SN. High fat diet-Induced obesity alters vitamin D metabolizing enzyme expression in mice. Biofactors 2015; 41(3): 175-182. https://doi.org/10.1002/biof.1211
  5. Bell NH, Shaw S, Turner RT. Evidence that 1,25-dihydroxyvitamin D3 inhibits the hepatic production of 25-hydroxyvitamin D in man. J Clin Invest 1984; 74(4): 1540-1544. https://doi.org/10.1172/JCI111568
  6. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72(3): 690-693. https://doi.org/10.1093/ajcn/72.3.690
  7. Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int 2013; 92(2): 77-98. https://doi.org/10.1007/s00223-012-9619-0
  8. Christodoulou S, Goula T, Ververidis A, Drosos G. Vitamin D and bone disease. BioMed Res Int 2013; 2013: 396541.
  9. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol 2010; 10(4): 482-496. https://doi.org/10.1016/j.coph.2010.04.001
  10. Samuel S, Sitrin MD. Vitamin D's role in cell proliferation and differentiation. Nutr Rev 2008; 66(10 Suppl 2): S116-S124. https://doi.org/10.1111/j.1753-4887.2008.00094.x
  11. Bell NH. Vitamin D-endocrine system. J Clin Invest 1985; 76(1): 1-6. https://doi.org/10.1172/JCI111930
  12. Henry HL. Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 2011; 25(4): 531-541. https://doi.org/10.1016/j.beem.2011.05.003
  13. Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H, et al. Parathyroid hormone activation of the 25-hydroxyvitamin D3-1α-hydroxylase gene promoter. Proc Natl Acad Sci U S A 1998; 95(4): 1387-1391. https://doi.org/10.1073/pnas.95.4.1387
  14. Stein MS, Flicker L, Scherer SC, Paton LM, O'Brien ML, Walton SC, et al. Relationships with serum parathyroid hormone in old institutionalized subjects. Clin Endocrinol (Oxf ) 2001; 54(5): 583-592. https://doi.org/10.1046/j.1365-2265.2001.01182.x
  15. Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone level is associated with body mass index. The 5th Tromso study. Eur J Endocrinol 2004; 151(2): 167-172. https://doi.org/10.1530/eje.0.1510167
  16. Gunther CW, Legowski PA, Lyle RM, Weaver CM, McCabe LD, McCabe GP, et al. Parathyroid hormone is associated with decreased fat mass in young healthy women. Int J Obes 2006; 30(1): 94-99. https://doi.org/10.1038/sj.ijo.0803066
  17. Smogorzewski M, Perna AF, Borum PR, Massry SG. Fatty acid oxidation in the myocardium: effects of parathyroid hormone and CRF. Kidney Int 1988; 34(6): 797-803. https://doi.org/10.1038/ki.1988.252
  18. Zemel MB. Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications. J Am Coll Nutr 2002; 21(2): 146S-151S. https://doi.org/10.1080/07315724.2002.10719212
  19. Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol 2007; 157(2): 225-232. https://doi.org/10.1530/EJE-07-0188
  20. Dong BJ. Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther 2005; 27(11): 1725-1751. https://doi.org/10.1016/j.clinthera.2005.11.015
  21. Nemeth EF, Heaton WH, Miller M, Fox J, Balandrin MF, Van Wagenen BC, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther 2004; 308(2): 627-635. https://doi.org/10.1124/jpet.103.057273
  22. Jung YS, Wu D, Smith D, Meydani SN, Han SN. Dysregulated 1,25-dihydroxyvitamin D levels in high-fat diet-induced obesity can be restored by changing to a lower-fat diet in mice. Nutr Res 2018; 53: 51-60. https://doi.org/10.1016/j.nutres.2018.03.008
  23. 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(1): 370-373. https://doi.org/10.1172/JCI111971
  24. Colloton M, Shatzen E, Miller G, Stehman-Breen C, Wada M, Lacey D, et al. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int 2005; 67(2): 467-476. https://doi.org/10.1111/j.1523-1755.2005.67103.x
  25. Lindberg JS, Culleton B, Wong G, Borah MF, Clark RV, Shapiro WB, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol 2005; 16(3): 800-807. https://doi.org/10.1681/ASN.2004060512
  26. Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys 2012; 523(1): 9-18. https://doi.org/10.1016/j.abb.2011.11.003
  27. Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, et al. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab 2005; 90(7): 4119-4123. https://doi.org/10.1210/jc.2005-0216
  28. Camozzi V, Frigo AC, Zaninotto M, Sanguin F, Plebani M, Boscaro M, et al. 25-Hydroxycholecalciferol response to single oral cholecalciferol loading in the normal weight, overweight, and obese. Osteoporos Int 2016; 27(8): 2593-2602. https://doi.org/10.1007/s00198-016-3574-y
  29. McCarty 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. Med Hypotheses 2003; 61(5-6): 535-542. https://doi.org/10.1016/S0306-9877(03)00227-5
  30. Shi H, Dirienzo D, Zemel MB. Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy-restricted aP2-agouti transgenic mice. FASEB J 2001; 15(2): 291-293. https://doi.org/10.1096/fj.00-0584fje
  31. Suda T, Shinki T, Kurokawa K. The mechanisms of regulation of vitamin D metabolism in the kidney. Curr Opin Nephrol Hypertens 1994; 3(1): 59-64. https://doi.org/10.1097/00041552-199401000-00008
  32. Ikeda K, Matsumoto T, Morita K, Yamato H, Takahashi H, Ezawa I, et al. The role of insulin in the stimulation of renal 1,25-dihydroxyvitamin D synthesis by parathyroid hormone in rats. Endocrinology 1987; 121(5): 1721-1726. https://doi.org/10.1210/endo-121-5-1721
  33. Kanno A, Asahara SI, Masuda K, Matsuda T, Kimura-Koyanagi M, Seino S, et al. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets. Biochem Biophys Res Commun 2015; 458(3): 681-686. https://doi.org/10.1016/j.bbrc.2015.02.024
  34. White JH. JAK3 talks down to renal 25-hydroxyvitamin D 1α-hydroxylase. Kidney Int 2015; 87(4): 678-679. https://doi.org/10.1038/ki.2014.380
  35. Umbach AT, Zhang B, Daniel C, Fajol A, Velic A, Hosseinzadeh Z, et al. Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism. Kidney Int 2015; 87(4): 728-737. https://doi.org/10.1038/ki.2014.371
  36. Mito N, Hosoda T, Kato C, Sato K. Change of cytokine balance in diet-induced obese mice. Metabolism 2000; 49(10): 1295-1300. https://doi.org/10.1053/meta.2000.9523
  37. Armbrecht HJ, Boltz MA, Hodam TL. PTH increases renal 25(OH)D3-1α-hydroxylase (CYP1α) mRNA but not renal 1,25(OH)2D3 production in adult rats. Am J Physiol Renal Physiol 2003; 284(5): F1032-F1036. https://doi.org/10.1152/ajprenal.00306.2002
  38. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 2010; 38(1): 96-109. https://doi.org/10.1177/0192623309356453
  39. Eo H, Park JE, Jeon YJ, Lim Y. Ameliorative effect of Ecklonia cava polyphenol extract on renal inflammation associated with aberrant energy metabolism and oxidative stress in high fat diet-induced obese mice. J Agric Food Chem 2017; 65(19): 3811-3818. https://doi.org/10.1021/acs.jafc.7b00357
  40. Olusi SO. Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans. Int J Obes 2002; 26(9): 1159-1164. https://doi.org/10.1038/sj.ijo.0802066
  41. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014; 21(3): 319-329. https://doi.org/10.1016/j.chembiol.2013.12.016
  42. Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci U S A 2013; 110(39): 15650-15655. https://doi.org/10.1073/pnas.1315006110