Thiamine: A Natural Peroxisome Proliferator-Activated Receptor Gamma
(PPAR-γ) Activator

Parasuraman   Aiya   Subramani; Firdose   Begum   Shaik; R.   Dinakaran   Michael; Kalpana      Panati; Venkata   Ramireddy   Narala

Abstract

Background: There has been increasing evidence of the correlation between thiamine deficiency and type 2 diabetes (T2D). T2D is a condition in which an individual’s insulin sensitivity is highly compromised. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated transcription factor etiologically relevant to T2D. We hypothesized that thiamine could be a PPAR-γ ligand and thus activate PPAR-γ and ameliorate T2D.

Objective: This study aims to establish thiamine as a PPAR-γ ligand via molecular docking and dynamics simulations (MDS) and thiamine’s ability to induce adipogenesis while upregulating PPAR-γ and AP-2 genes using in vitro assays.

Methods: Thiamine/PPAR-γ binding was studied using Schrödinger’s Glide. The bound complex was simulated in the OPLS 2005 force field using Desmond. 3T3-L1 preadipocyte cells were differentiated in the presence of thiamine and rosiglitazone and stained with Oil Red O. Nuclear protein from the differentiated cells was used to study the binding of the PPAR-γ response element (PPRE) using an ELISA-based assay. mRNA from differentiated cells was used to study the expression of genes using quantitative RTPCR.

Results: In silico docking shows that thiamine binds with PPAR-γ. MDS indicate that the interactions between thiamine and PPAR-γ are stable over a significant period. Thiamine induces the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner and enhances the PPRE-binding activity of PPAR-γ. Thiamine treatment significantly increases the mRNA levels of PPAR-γ and AP-2 genes.

Conclusion: Our results show that thiamine is a PPAR-γ ligand. Animal studies and clinical trials are required to corroborate the results obtained.

Keywords: PPAR-γ, thiamine, type 2 diabetes, molecular dynamics simulations, adipocytes differentiation, natural ligand.

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[1] 
Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; Shaw, J.E.; Bright, D.; Williams, R. Global and regional diabetes
prevalence estimates for 2019 and projections for 2030 and
2045: Results from the International Diabetes Federation Diabetes
Atlas, 9th edition. Diabetes Res. Clin. Pract.,  2019, 157, 107843.
[http://dx.doi.org/10.1016/j.diabres.2019.107843] 
[2] 
Frasca, D.; Blomberg, B.B.; Paganelli, R. Aging, obesity, and inflammatory age-related diseases. Front. Immunol.,  2017, 8, 1745.
[http://dx.doi.org/10.3389/fimmu.2017.01745] [PMID: 29270179] 
[3] 
Medina-Remón, A.; Kirwan, R.; Lamuela-Raventós, R.M.; Estruch, R. Dietary patterns and the risk of obesity, type 2 diabetes mellitus, cardiovascular diseases, asthma, and neurodegenerative diseases. Crit. Rev. Food Sci. Nutr.,  2018, 58(2), 262-296.
[http://dx.doi.org/10.1080/10408398.2016.1158690] [PMID: 27127938] 
[4] 
Jia, X.; Yang, Y.; Chen, Y.; Xia, Z.; Zhang, W.; Feng, Y.; Li, Y.; Tan, J.; Xu, C.; Zhang, Q.; Deng, H.; Shi, X. Multivariate analysis of ge-nome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA. Int. J. Cardiol.,  2019, 283, 144-150.
[http://dx.doi.org/10.1016/j.ijcard.2018.10.102] [PMID: 30459114] 
[5] 
Kolb, H.; Martin, S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med.,  2017, 15(1), 131.
[http://dx.doi.org/10.1186/s12916-017-0901-x] [PMID: 28720102] 
[6] 
Gulley, L.D.; Shomaker, L.B. Depression in youth-onset Type 2 Diabetes. Curr. Diab. Rep.,  2020, 20(10), 51.
[http://dx.doi.org/10.1007/s11892-020-01334-8] [PMID: 32857299] 
[7] 
Manios, Y. Lambrinou, C-P.; Mavrogianni, C.; Cardon, G.; Lindström, J.; Iotova, V.; Tankova, T.; Rurik, I.; Stappen, V.V.; Kivelä, J.; Mateo-Gallego, R.; Moreno, L.A.; Makrilakis, K.; Androutsos, O. Lifestyle changes observed among adults participating in a family- and community-based intervention for diabetes prevention in Europe: The 1st year results of the feel4diabetes-study. Nutrients,  2020, 12(7), 1949.
[http://dx.doi.org/10.3390/nu12071949] [PMID: 32629949] 
[8] 
Gibbons, C.; Blundell, J.; Tetens Hoff, S.; Dahl, K.; Bauer, R.; Baekdal, T. Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes. Diabetes Obes. Metab.,  2021, 23(2), 581-588.
[http://dx.doi.org/10.1111/dom.14255] [PMID: 33184979] 
[9] 
MacDonald, C.S.; Nielsen, S.M.; Bjørner, J.; Johansen, M.Y.; Christensen, R.; Vaag, A.; Lieberman, D.E.; Pedersen, B.K.; Langberg, H.; Ried-Larsen, M.; Midtgaard, J. One-year intensive lifestyle intervention and improvements in health-related quality of life and mental health in persons with type 2 diabetes: A secondary analysis of the U-TURN randomized controlled trial. BMJ Open Diabetes Res. Care,  2021, 9(1), e001840.
[http://dx.doi.org/10.1136/bmjdrc-2020-001840] [PMID: 33441418] 
[10] 
Carpenter, K.J. The discovery of thiamin. Ann. Nutr. Metab.,  2012, 61(3), 219-223.
[http://dx.doi.org/10.1159/000343109] [PMID: 23183292] 
[11] 
Fitzpatrick, T.B.; Thore, S. Complex behavior: From cannibalism to suicide in the vitamin B1 biosynthesis world. Curr. Opin. Struct. Biol.,  2014, 29, 34-43.
[http://dx.doi.org/10.1016/j.sbi.2014.08.014] [PMID: 25260119] 
[12] 
Eshak, E.S.; Arafa, A.E. Thiamine deficiency and cardiovascular disorders. Nutr. Metab. Cardiovasc. Dis.,  2018, 28(10), 965-972.
[http://dx.doi.org/10.1016/j.numecd.2018.06.013] [PMID: 30143411] 
[13] 
Page, G.L.; Laight, D.; Cummings, M.H. Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose me-tabolism and vascular disease. Int. J. Clin. Pract.,  2011, 65(6), 684-690.
[http://dx.doi.org/10.1111/j.1742-1241.2011.02680.x] [PMID: 21564442] 
[14] 
Karkabounas, S.; Papadopoulos, N.; Anastasiadou, C.; Gubili, C.; Peschos, D.; Daskalou, T.; Fikioris, N.; Simos, Y.V.; Kontargiris, E.; Gianakopoulos, X.; Ragos, V.; Chatzidimitriou, M. Effects of α-lipoic acid, carnosine, and thiamine supplementation in obese patients with type 2 diabetes mellitus: A randomized, double-blind study. J. Med. Food,  2018, 21(12), 1197-1203.
[http://dx.doi.org/10.1089/jmf.2018.0007] [PMID: 30311825] 
[15] 
Beltramo, E.; Mazzeo, A.; Lopatina, T.; Trento, M.; Porta, M. Thiamine transporter 2 is involved in high glucose-induced damage and altered thiamine availability in cell models of diabetic retinopathy. Diabetes Vasc. Dis. Res.,  2020, 17(1), 1479164119878427.
[16] 
Jungtrakoon, P.; Shirakawa, J.; Buranasupkajorn, P.; Gupta, M.K.; De Jesus, D.F.; Pezzolesi, M.G.; Panya, A.; Hastings, T.; Chanprasert, C.; Mendonca, C.; Kulkarni, R.N.; Doria, A. Loss-of-function mutation in thiamine transporter 1 in a family with autosomal dominant dia-betes. Diabetes,  2019, 68(5), 1084-1093.
[http://dx.doi.org/10.2337/db17-0821] [PMID: 30833467] 
[17] 
Beltramo, E.; Berrone, E.; Tarallo, S.; Porta, M. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol.,  2008, 45(3), 131-141.
[http://dx.doi.org/10.1007/s00592-008-0042-y] [PMID: 18581039] 
[18] 
Malecka, S.A.; Poprawski, K.; Bilski, B. Prophylactic and therapeutic
application of thiamine (vitamin B1)-a new point of view. Wiadomosci lekarskie (Warsaw, Poland: 1960),  2006, 59(5-6), 383-387.
[19] 
Rabbani, N.; Thornalley, P.J. Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. Diabetes Obes. Metab.,  2011, 13(7), 577-583.
[http://dx.doi.org/10.1111/j.1463-1326.2011.01384.x] [PMID: 21342411] 
[20] 
Karachalias, N.; Babaei-Jadidi, R.; Kupich, C.; Ahmed, N.; Thornalley, P.J. High-dose thiamine therapy counters dyslipidemia and ad-vanced glycation of plasma protein in streptozotocin-induced diabetic rats. Ann. N. Y. Acad. Sci.,  2005, 1043, 777-783.
[http://dx.doi.org/10.1196/annals.1333.090] [PMID: 16037305] 
[21] 
Thornalley, P.J. The potential role of thiamine. The potential role of thiamine (vitamin B1) in diabetic complications. Curr. Diabetes Rev.,  2005, 1(3), 287-298.
[http://dx.doi.org/10.2174/157339905774574383] [PMID: 18220605] 
[22] 
Hoyumpa, A.M., Jr Mechanisms of thiamin deficiency in chronic alcoholism. Am. J. Clin. Nutr.,  1980, 33(12), 2750-2761.
[http://dx.doi.org/10.1093/ajcn/33.12.2750] [PMID: 6254354] 
[23] 
Vieregge, P.; Stuhlmann, W. Diabetic coma and Wernicke-Korsakoff syndrome. On the clinical significance of acquired thiamine deficien-cy. Fortschr. Neurol. Psychiatr.,  1987, 55(4), 130-139.
[http://dx.doi.org/10.1055/s-2007-1001815] [PMID: 3596452] 
[24] 
Bermúdez, V.; Finol, F.; Parra, N.; Parra, M.; Pérez, A.; Peñaranda, L.; Vílchez, D.; Rojas, J.; Arráiz, N.; Velasco, M. PPAR-gamma ago-nists and their role in type 2 diabetes mellitus management. Am. J. Ther.,  2010, 17(3), 274-283.
[http://dx.doi.org/10.1097/MJT.0b013e3181c08081] [PMID: 20216208] 
[25] 
Subramani, P.A.; Reddy, M.C.; Narala, V.R. The need for physiologically relevant peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligands. Endocr. Metab. Immune Disord. Drug Targets,  2013, 13(2), 175-183.
[http://dx.doi.org/10.2174/18715303113139990003] [PMID: 23713695] 
[26] 
Balakumar, P.; Rohilla, A.; Krishan, P.; Solairaj, P.; Thangathirupathi, A. The multifaceted therapeutic potential of benfotiamine. Pharmacol. Res.,  2010, 61(6), 482-488.
[http://dx.doi.org/10.1016/j.phrs.2010.02.008] [PMID: 20188835] 
[27] 
Nolte, R.T.; Wisely, G.B.; Westin, S.; Cobb, J.E.; Lambert, M.H.; Kurokawa, R.; Rosenfeld, M.G.; Willson, T.M.; Glass, C.K.; Milburn, M.V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature,  1998, 395(6698), 137-143.
[http://dx.doi.org/10.1038/25931] [PMID: 9744270] 
[28] 
Sastry, G.M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influ-ence on virtual screening enrichments. J. Comput. Aided Mol. Des.,  2013, 27(3), 221-234.
[http://dx.doi.org/10.1007/s10822-013-9644-8] [PMID: 23579614] 
[29] 
Banks, J.L.; Beard, H.S.; Cao, Y.; Cho, A.E.; Damm, W.; Farid, R.; Felts, A.K.; Halgren, T.A.; Mainz, D.T.; Maple, J.R.; Murphy, R.; Philipp, D.M.; Repasky, M.P.; Zhang, L.Y.; Berne, B.J.; Friesner, R.A.; Gallicchio, E.; Levy, R.M. Integrated Modeling Program, Applied Chemical Theory (IMPACT). J. Comput. Chem.,  2005, 26(16), 1752-1780.
[http://dx.doi.org/10.1002/jcc.20292] [PMID: 16211539] 
[30] 
Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inform. and Model-ing,  2011, 51(10), 2778-2786.
[31] 
Bowers, K.J.; Chow, E.; Xu, H.; Dror, R.O.; Eastwood, M.P.; Gregersen, B.A.; Klepeis, J.L.; Kolossvary, I.; Moraes, M.A.; Sacerdoti, F.D.; Salmon, J.K.; Shan, Y.; Shaw, D.E. Scalable algorithms
for molecular dynamics simulations on commodity clusters.
In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing,
11-17 Nov. 2006 Tampa, Florida 
[http://dx.doi.org/10.1145/1188455.1188544] 
[32] 
Berendsen, H.J.C.; Postma, J.P.M.; van Gunsteren, W.F.; Hermans, J. Interaction Models for Water in Relation to Protein Hydration.In: Intermolecular Forces; Pullman, B., Ed.; Springer: The Netherlands, 1981, Vol. 14, pp. 331-342.
[http://dx.doi.org/10.1007/978-94-015-7658-1_21] 
[33] 
Evans, D.J.; Holian, B.L. The Nose–Hoover thermostat. J. Chem. Phys.,  1985, 83(8), 4069-4074.
[http://dx.doi.org/10.1063/1.449071] 
[34] 
Martyna, G.J.; Tobias, D.J.; Klein, M.L. Constant pressure molecular dynamics algorithms. J. Chem. Phys.,  1994, 101(5), 4177-4189.
[http://dx.doi.org/10.1063/1.467468] 
[35] 
Essmann, U.; Perera, L.; Berkowitz, M.L.; Darden, T.; Lee, H.; Pedersen, L.G. A smooth particle mesh Ewald method. J. Chem. Phys.,  1995, 103(19), 8577-8593.
[http://dx.doi.org/10.1063/1.470117] 
[36] 
Panati, K.; Subramani, P.A.; Reddy, M.M.; Derangula, M.; Arva Tatireddigari, V.R.R.; Kolliputi, N.; Narala, V.R. The nitrated fatty acid, 10-nitrooleate inhibits the neutrophil chemotaxis via peroxisome proliferator-activated receptor gamma in CLP-induced sepsis in mice. Int. Immunopharmacol.,  2019, 72, 159-165.
[http://dx.doi.org/10.1016/j.intimp.2019.04.001] [PMID: 30981081] 
[37] 
Lascar, N.; Brown, J.; Pattison, H.; Barnett, A.H.; Bailey, C.J.; Bellary, S. Type 2 diabetes in adolescents and young adults. Lancet Diabetes Endocrinol.,  2018, 6(1), 69-80.
[http://dx.doi.org/10.1016/S2213-8587(17)30186-9] [PMID: 28847479] 
[38] 
Ramzan, S.; Timmins, P.; Hasan, S.S.; Babar, Z.U. Cost analysis of type 2 diabetes mellitus treatment in economically developed coun-tries. Expert Rev. Pharmacoecon. Outcomes Res.,  2019, 19(1), 5-14.
[http://dx.doi.org/10.1080/14737167.2018.1513790] [PMID: 30146917] 
[39] 
Artasensi, A.; Pedretti, A.; Vistoli, G.; Fumagalli, L. Type 2 Diabetes Mellitus: A review of multi-target drugs. Molecules,  2020, 25(8), E1987.
[http://dx.doi.org/10.3390/molecules25081987] [PMID: 32340373] 
[40] 
Nix, W.A.; Zirwes, R.; Bangert, V.; Kaiser, R.P.; Schilling, M.; Hostalek, U.; Obeid, R. Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes Res. Clin. Pract.,  2015, 107(1), 157-165.
[http://dx.doi.org/10.1016/j.diabres.2014.09.058] [PMID: 25458341] 
[41] 
Chikowore, T.; Pisa, P.T.; van Zyl, T.; Feskens, E.J.; Wentzel-Viljoen, E.; Conradie, K.R. Nutrient patterns associated with fasting glucose and glycated haemoglobin levels in a black South African population. Nutrients,  2017, 9(1), E9.
[http://dx.doi.org/10.3390/nu9010009] [PMID: 28106816] 
[42] 
Cinici, E.; Dilekmen, N.; Senol, O. Arpalı E.; Cinici, O.; Tanas, S. Blood thiamine pyrophosphate concentration and its correlation with the stage of diabetic retinopathy. Int. Ophthalmol.,  2020, 40(12), 3279-3284.
[http://dx.doi.org/10.1007/s10792-020-01513-2] [PMID: 32715366] 
[43] 
Ziegler, D.; Papanas, N.; Schnell, O.; Nguyen, B.D.T.; Nguyen, K.T.; Kulkantrakorn, K.; Deerochanawong, C. Current concepts in the management of diabetic polyneuropathy. J. Diabetes Investig.,  2021, 12(4), 464-475.
[PMID: 32918837] 
[44] 
Feng, C.; Li, D.; Chen, M.; Jiang, L.; Liu, X.; Li, Q.; Geng, C.; Sun, X.; Yang, G.; Zhang, L.; Yao, X. Citreoviridin induces myocardial apoptosis through PPAR-γ-mTORC2-mediated autophagic pathway and the protective effect of thiamine and selenium. Chem. Biol. Interact.,  2019, 311, 108795.
[http://dx.doi.org/10.1016/j.cbi.2019.108795] [PMID: 31419397] 
[45] 
Xu, H.E.; Lambert, M.H.; Montana, V.G.; Plunket, K.D.; Moore, L.B.; Collins, J.L.; Oplinger, J.A.; Kliewer, S.A.; Gampe, R.T., Jr; McKee, D.D.; Moore, J.T.; Willson, T.M. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated recep-tors. Proc. Natl. Acad. Sci. USA,  2001, 98(24), 13919-13924.
[http://dx.doi.org/10.1073/pnas.241410198] [PMID: 11698662] 
[46] 
Gim, H.J.; Choi, Y.S.; Li, H.; Kim, Y.J.; Ryu, J.H.; Jeon, R. Identification of a novel PPAR-γ agonist through a scaffold tuning approach. Int. J. Mol. Sci.,  2018, 19(10), E3032.
[http://dx.doi.org/10.3390/ijms19103032] [PMID: 30287791] 
[47] 
Durrant, J.D.; McCammon, J.A. Molecular dynamics simulations and drug discovery. BMC Biol.,  2011, 9(1), 71.
[http://dx.doi.org/10.1186/1741-7007-9-71] [PMID: 22035460] 
[48] 
Narala, V.R.; Adapala, R.K.; Suresh, M.V.; Brock, T.G.; Peters-Golden, M.; Reddy, R.C. Leukotriene B4 is a physiologically relevant en-dogenous peroxisome proliferator-activated receptor-alpha agonist. J. Biol. Chem.,  2010, 285(29), 22067-22074.
[49] 
Sullivan, H-J.; Wang, X.; Nogle, S.; Liao, S.; Wu, C. To probe full and partial activation of human peroxisome proliferator-activated recep-tors by pan-agonist chiglitazar using molecular dynamics simulations. PPAR Res.,  2020, 2020, 5314187.
[http://dx.doi.org/10.1155/2020/5314187] [PMID: 32308671] 
[50] 
Hu, S.; He, W.; Du, X.; Huang, Y.; Fu, Y.; Yang, Y.; Hu, C.; Li, S.; Wang, Q.; Wen, Q.; Zhou, X.; Zhou, C.; Zhong, X-P.; Ma, L. Vitamin B1 helps to limit Mycobacterium tuberculosis growth via regulating innate immunity in a peroxisome proliferator-activated receptor-γ-dependent manner. Front. Immunol.,  1778, 2018, 9.
[PMID: 30166982] 
[51] 
Rival, Y.; Stennevin, A.; Puech, L.; Rouquette, A.; Cathala, C.; Lestienne, F.; Dupont-Passelaigue, E.; Patoiseau, J.F.; Wurch, T.; Junquéro, D. Human adipocyte fatty acid-binding protein (aP2) gene promoter-driven reporter assay discriminates nonlipogenic peroxisome prolif-erator-activated receptor gamma ligands. J. Pharmacol. Exp. Ther.,  2004, 311(2), 467-475.
[http://dx.doi.org/10.1124/jpet.104.068254] [PMID: 15273253] 

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DOI https://dx.doi.org/10.2174/1570180819666220127121403	Print ISSN 1570-1808
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Thiamine: A Natural Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) Activator

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