Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines
Autoři:
Ryoko Takei aff001; Tomoaki Inoue aff001; Noriyuki Sonoda aff001; Motoyuki Kohjima aff001; Misato Okamoto aff001; Ryuichi Sakamoto aff001; Toyoshi Inoguchi aff002; Yoshihiro Ogawa aff001
Působiště autorů:
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
aff001; Fukuoka City Health Promotion Support Center, Fukuoka, Japan
aff002; Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
aff003
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0223302
Souhrn
Objective
Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model.
Method
Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues.
Results
In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice.
Conclusions
Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.
Klíčová slova:
Adipose tissue – Fats – Inflammation – Obesity – bilirubin – Adipocytes
Zdroje
1. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994;17(9):961–9. doi: 10.2337/diacare.17.9.961 7988316
2. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med. 1995;122(7):481–6. doi: 10.7326/0003-4819-122-7-199504010-00001 7872581
3. Banerji MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes Relat Metab Disord. 1995;19(12):846–50. 8963350
4. Despres JP, Lemieux S, Lamarche B, Prud'homme D, Moorjani S, Brun LD, et al. The insulin resistance-dyslipidemic syndrome: contribution of visceral obesity and therapeutic implications. Int J Obes Relat Metab Disord. 1995;19 Suppl 1:S76–86.
5. Boyko EJ, Fujimoto WY, Leonetti DL, Newell-Morris L. Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans. Diabetes Care. 2000;23(4):465–71. doi: 10.2337/diacare.23.4.465 10857936
6. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11(11):738–49. doi: 10.1038/nri3071 21984069
7. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46. doi: 10.1146/annurev-physiol-021909-135846 20148674
8. Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA. 2007;298(12):1398–400. doi: 10.1001/jama.298.12.1398-b 17895455
9. Ohnaka K, Kono S, Inoguchi T, Yin G, Morita M, Adachi M, et al. Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract. 2010;88(1):103–10. doi: 10.1016/j.diabres.2009.12.022 20083320
10. Hinds TD Jr., Hosick PA, Chen S, Tukey RH, Hankins MW, Nestor-Kalinoski A, et al. Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am J Physiol Endocrinol Metab. 2017;312(4):E244–E52. doi: 10.1152/ajpendo.00396.2016 28096081
11. Hinds TD Jr., Burns KA, Hosick PA, McBeth L, Nestor-Kalinoski A, Drummond HA, et al. Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha. J Biol Chem. 2016;291(48):25179–91 doi: 10.1074/jbc.M116.731703 27738106
12. Cimini FA, Arena A, Barchetta I, Tramutola A, Ceccarelli V, Lanzillotta C, et al. Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1490–501. doi: 10.1016/j.bbadis.2019.02.021 30826467
13. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043–6. doi: 10.1126/science.3029864 3029864
14. Inoguchi T, Sonoda N, Maeda Y. Bilirubin as an important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes: a new aspect on old molecule. Diabetol Int. 2016;7(4):338–41. doi: 10.1007/s13340-016-0288-5 30603284
15. Ikeda N, Inoguchi T, Sonoda N, Fujii M, Takei R, Hirata E, et al. Biliverdin protects against the deterioration of glucose tolerance in db/db mice. Diabetologia. 2011;54(8):2183–91. doi: 10.1007/s00125-011-2197-2 21614569
16. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23(1):57–63. doi: 10.2337/diacare.23.1.57 10857969
17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. doi: 10.1007/bf00280883 3899825
18. Sackmann-Sala L, Berryman DE, Munn RD, Lubbers ER, Kopchick JJ. Heterogeneity among white adipose tissue depots in male C57BL/6J mice. Obesity (Silver Spring). 2012;20(1):101–11.
19. Stubbins RE, Najjar K, Holcomb VB, Hong J, Nunez NP. Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance. Diabetes Obes Metab. 2012;14(1):58–66. doi: 10.1111/j.1463-1326.2011.01488.x 21834845
20. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91. doi: 10.1126/science.7678183 7678183
21. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–50. doi: 10.1210/jcem.83.3.4660 9506738
22. Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K, et al. HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol. 2017;454:103–11. doi: 10.1016/j.mce.2017.06.012 28619625
23. Stocker R. Antioxidant activities of bile pigments. Antioxid Redox Signal. 2004;6(5):841–9. doi: 10.1089/ars.2004.6.841 15345144
24. Fujii M, Inoguchi T, Sasaki S, Maeda Y, Zheng J, Kobayashi K, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int. 2010;78(9):905–19. doi: 10.1038/ki.2010.265 20686447
25. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30. doi: 10.1172/JCI19451 14679177
26. Bai Y, Sun Q. Macrophage recruitment in obese adipose tissue. Obes Rev. 2015;16(2):127–36. doi: 10.1111/obr.12242 25586506
27. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808. doi: 10.1172/JCI19246 14679176
28. Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N, et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol. 2005;142(3):481–9. doi: 10.1111/j.1365-2249.2005.02934.x 16297160
29. Liu J, Dong H, Zhang Y, Cao M, Song L, Pan Q, et al. Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARgamma Levels. Sci Rep. 2015;5:9886. doi: 10.1038/srep09886 26017184
30. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752–61. doi: 10.1172/JCI21625 15599400
31. Stec DE, John K, Trabbic CJ, Luniwal A, Hankins MW, Baum J, et al. Bilirubin Binding to PPARalpha Inhibits Lipid Accumulation. PLoS One. 2016;11(4):e0153427. doi: 10.1371/journal.pone.0153427 27071062
32. Hinds TD Jr., Stec DE. Bilirubin, a Cardiometabolic Signaling Molecule. Hypertension. 2018;72(4):788–95. doi: 10.1161/HYPERTENSIONAHA.118.11130 30354722
33. Gordon DM, Blomquist TM, Miruzzi SA, McCullumsmith R, Stec DE, Hinds TD Jr. RNA sequencing in human HepG2 hepatocytes reveals PPAR-alpha mediates transcriptome responsiveness of bilirubin. Physiol Genomics. 2019;51(6):234–40. doi: 10.1152/physiolgenomics.00028.2019 31074682
34. Hinds TD Jr., Sodhi K, Meadows C, Fedorova L, Puri N, Kim DH, et al. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity (Silver Spring). 2014;22(3):705–12.
Článek vyšel v časopise
PLOS One
2019 Číslo 10
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