Interaction between adipocytes and B lymphocytes in human metabolic diseases

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Diseases associated with disorders of carbohydrate and fat metabolism are widespread in the modern world. An essential factor in the pathogenesis of such diseases is the interaction between the cells of adipose tissue, adipocytes, and immune system cells. A long-term increase in glucose and fatty acids leads to adipocyte hypertrophy and increased expression of proinflammatory cytokines and adipokines by these cells. As a result, immune cells acquire a pro-inflammatory phenotype, and new leukocytes are recruited. Inflammation of adipose tissue leads to insulin resistance and stimulates the formation of atherosclerotic plaques and the development of autoimmune processes. New studies show that different groups of B lymphocytes play an essential role in the regulation of inflammation in adipose tissue. A decrease in B2 type lymphocytes suppresses the development of a number of metabolic diseases, whereas decreased numbers of regulatory B lymphocytes and B1 lymphocytes are associated with an increased pathology. Recent studies showed that adipocytes influence B lymphocyte activity both directly and by altering the activity of other immune cells. These findings provide a better understanding of the molecular mechanisms of human pathologies associated with impaired carbohydrate and lipid metabolism, such as type 2 diabetes mellitus.

About the authors

E. M Stasevich

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: shvarec@yandex.ru
119991 Moscow, Russia

E. A Zheremyan

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: shvarec@yandex.ru
119991 Moscow, Russia

D. V Kuprash

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: shvarec@yandex.ru
119991 Moscow, Russia

A. M Schwartz

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences;Moscow Institute of Physics and Technology

Email: shvarec@yandex.ru
119991 Moscow, Russia;141701 Moscow, Russia

References

  1. Shen, H., Kreisel, D., and Goldstein, D. R. (2013) Processes of sterile inflammation, J. Immunol., 191, 2857-2863, doi: 10.4049/jimmunol.1301539.
  2. Srikakulapu, P., and McNamara, C. A. (2020) B lymphocytes and adipose tissue inflammation, Arterioscler. Thromb. Vasc. Biol., 40, 1110-1122, doi: 10.1161/ATVBAHA.119.312467.
  3. Song, J., and Deng, T. (2020) The adipocyte and adaptive immunity, Front. Immunol., 11, 593058, doi: 10.3389/fimmu.2020.593058.
  4. Frühbeck, G. (2008) Overview of adipose tissue and its role in obesity and metabolic disorders, Methods Mol. Biol., 456, 1-22, doi: 10.1007/978-1-59745-245-8_1.
  5. Ansel, K. M., Harris, R. B. S., and Cyster, J. G. (2002) CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity, Immunity, 16, 67-76, doi: 10.1016/s1074-7613(01)00257-6.
  6. Benoit, M., Desnues, B., and Mege, J.-L. (2008) Macrophage polarization in bacterial infections, J. Immunol., 181, 3733-3739, doi: 10.4049/jimmunol.181.6.3733.
  7. Mancuso, P. (2016) The role of adipokines in chronic inflammation, ImmunoTargets Ther., 5, 47-56, doi: 10.2147/ITT.S73223.
  8. Wong, S.-C., Puaux, A.-L., Chittezhath, M., Shalova, I., Kajiji, T. S., Wang, X., et al. (2010) Macrophage polarization to a unique phenotype driven by B cells, Eur. J. Immunol., 40, 2296-2307, doi: 10.1002/eji.200940288.
  9. Harmon, D. B., Srikakulapu, P., Kaplan, J. L., Oldham, S. N., McSkimming, C., Garmey, J. C., et al. (2016) Protective role for B-1b B cells and IgM in obesity-associated inflammation, glucose intolerance, and insulin resistance, Arterioscler. Thromb. Vasc. Biol., 36, 682-691, doi: 10.1161/ATVBAHA.116.307166.
  10. Miller, Y. I., Choi, S.-H., Wiesner, P., Fang, L., Harkewicz, R., Hartvigsen, K., et al. (2011) Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity, Circ. Res., 108, 235-248, doi: 10.1161/CIRCRESAHA.110.223875.
  11. Srikakulapu, P., Upadhye, A., Drago, F., Perry, H. M., Bontha, S. V., McSkimming, C., et al. (2021) Chemokine receptor-6 promotes B-1 cell trafficking to perivascular adipose tissue, local IgM production and atheroprotection, Front. Immunol., 12, 636013, doi: 10.3389/fimmu.2021.636013.
  12. Ying, W., Wollam, J., Ofrecio, J. M., Bandyopadhyay, G., El Ouarrat, D., Lee, Y. S., et al. (2017) Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling, J. Clin. Invest., 127, 1019-1030, doi: 10.1172/JCI90350.
  13. Werz, O., Gerstmeier, J., Libreros, S., De la Rosa, X., Werner, M., Norris, P. C., et al. (2018) Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity, Nat. Commun., 9, 59, doi: 10.1038/s41467-017-02538-5.
  14. DeFuria, J., Belkina, A. C., Jagannathan-Bogdan, M., Snyder-Cappione, J., Carr, J. D., Nersesova, Y. R., et al. (2013) B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile, Proc. Natl. Acad. Sci. USA, 110, 5133-5138, doi: 10.1073/pnas.1215840110.
  15. Zhai, X., Qian, G., Wang, Y., Chen, X., Lu, J., Zhang, Y., et al. (2016) Elevated B cell activation is associated with type 2 diabetes development in obese subjects, Cell. Physiol. Biochem., 38, 1257-1266, doi: 10.1159/000443073.
  16. Arkatkar, T., Du, S. W., Jacobs, H. M., Dam, E. M., Hou, B., Buckner, J. H., et al. (2017) B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity, J. Exp. Med., 214, 3207-3217, doi: 10.1084/jem.20170580.
  17. Wueest, S., Laesser, C. I., Böni-Schnetzler, M., Item, F., Lucchini, F. C., Borsigova, M., et al. (2018) IL-6-type cytokine signaling in adipocytes induces intestinal GLP-1 secretion, Diabetes, 67, 36-45, doi: 10.2337/db17-0637.
  18. Akbari, M., and Hassan-Zadeh, V. (2018) IL-6 signalling pathways and the development of type 2 diabetes, Inflammopharmacology, 26, 685-698, doi: 10.1007/s10787-018-0458-0.
  19. Gómez-Touriño, I., Camiña-Darriba, F., Otero-Romero, I., Rodríguez, M. A., Hernández-Fernández, A., González-Fernández, A., et al. (2010) Autoantibodies to glial fibrillary acid protein and S100beta in diabetic patients, Diabet. Med., 27, 246-248, doi: 10.1111/j.1464-5491.2009.02911.x.
  20. Pietropaolo, M., Barinas-Mitchell, E., Pietropaolo, S. L., Kuller, L. H., and Trucco, M. (2000) Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes, Diabetes, 49, 32-38, doi: 10.2337/diabetes.49.1.32.
  21. Turner, R., Stratton, I., Horton, V., Manley, S., Zimmet, P., Mackay, I. R., et al. (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group, Lancet (London, England), 350, 1288-1293, doi: 10.1016/s0140-6736(97)03062-6.
  22. Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S., and Bhan, A. K. (2002) Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation, Immunity, 16, 219-230, doi: 10.1016/s1074-7613(02)00274-1.
  23. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D., and Anderton, S. M. (2002) B cells regulate autoimmunity by provision of IL-10, Nat. Immunol., 3, 944-950, doi: 10.1038/ni833.
  24. Tian, J., Zekzer, D., Hanssen, L., Lu, Y., Olcott, A., and Kaufman, D. L. (2001) Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice, J. Immunol., 167, 1081-1089, doi: 10.4049/jimmunol.167.2.1081.
  25. Parekh, V. V., Prasad, D. V. R., Banerjee, P. P., Joshi, B. N., Kumar, A., and Mishra, G. C. (2003) B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-beta 1, J. Immunol., 170, 5897-5911, doi: 10.4049/jimmunol.170.12.5897.
  26. Wang, R.-X., Yu, C.-R., Dambuza, I. M., Mahdi, R. M., Dolinska, M. B., Sergeev, Y. V., et al. (2014) Interleukin-35 induces regulatory B cells that suppress autoimmune disease, Nat. Med., 20, 633-641, doi: 10.1038/nm.3554.
  27. Asadullah, K., Sterry, W., and Volk, H. D. (2003) Interleukin-10 therapy - review of a new approach, Pharmacol. Rev., 55, 241-269, doi: 10.1124/pr.55.2.4.
  28. Shang, J., Zha, H., and Sun, Y. (2020) Phenotypes, functions, and clinical relevance of regulatory B cells in cancer, Front. Immunol., 11, 582657, doi: 10.3389/fimmu.2020.582657.
  29. Jansen, K., Cevhertas, L., Ma, S., Satitsuksanoa, P., Akdis, M., and van de Veen, W. (2021) Regulatory B cells, A to Z, Allergy, 76, 2699-2715, doi: 10.1111/all.14763.
  30. Nishimura, S., Manabe, I., Takaki, S., Nagasaki, M., Otsu, M., Yamashita, H., et al. (2013) Adipose natural regulatory B cells negatively control adipose tissue inflammation, Cell Metab., 18, 759-766, doi: 10.1016/j.cmet.2013.09.017.
  31. Ghazarian, M., Luck, H., Revelo, X. S., Winer, S., and Winer, D. A. (2015) Immunopathology of adipose tissue during metabolic syndrome, Turk Patoloji Derg., 31 Suppl 1, 172-180, doi: 10.5146/tjpath.2015.01323.
  32. Garcia, S. G., Sandoval-Hellín, N., Clos-Sansalvador, M., Carreras-Planella, L., Morón-Font, M., Guerrero, D., et al. (2022) Mesenchymal stromal cells induced regulatory B cells are enriched in extracellular matrix genes and IL-10 independent modulators, Front. Immunol., 13, 957797, doi: 10.3389/fimmu.2022.957797.
  33. Shen, L., Chng, M. H. Y., Alonso, M. N., Yuan, R., Winer, D. A., and Engleman, E. G. (2015) B-1a lymphocytes attenuate insulin resistance, Diabetes, 64, 593-603, doi: 10.2337/db14-0554.
  34. Capasso, M., Rashed Alyahyawi, A., and Spear, S. (2015) Metabolic control of B cells: more questions than answers, Front. Immunol., 6, 80, doi: 10.3389/fimmu.2015.00080.
  35. Fasshauer, M., and Blüher, M. (2015) Adipokines in health and disease, Trends Pharmacol. Sci., 36, 461-470, doi: 10.1016/j.tips.2015.04.014.
  36. Reiche, M. E., Poels, K., Bosmans, L. A., Vos, W. G., Van Tiel, C. M., Gijbels, M. J. J., et al. (2022) Adipocytes control haematopoiesis and inflammation through CD40 signaling, Haematologica, doi: 10.3324/haematol.2022.281482.
  37. Szumilas, K., Szumilas, P., Słuczanowska-Głąbowska, S., Zgutka, K., and Pawlik, A. (2020) Role of adiponectin in the pathogenesis of rheumatoid arthritis, Int. J. Mol. Sci., 21, 8265, doi: 10.3390/ijms21218265.
  38. Bennett, B. D., Solar, G. P., Yuan, J. Q., Mathias, J., Thomas, G. R., and Matthews, W. (1996) A role for leptin and its cognate receptor in hematopoiesis, Curr. Biol., 6, 1170-1180, doi: 10.1016/s0960-9822(02)70684-2.
  39. Claycombe, K., King, L. E., and Fraker, P. J. (2008) A role for leptin in sustaining lymphopoiesis and myelopoiesis, Proc. Natl. Acad. Sci. USA, 105, 2017-2021, doi: 10.1073/pnas.0712053105.
  40. Lam, Q. L. K., Wang, S., Ko, O. K. H., Kincade, P. W., and Lu, L. (2010) Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1, Proc. Natl. Acad. Sci. USA, 107, 13812-13817, doi: 10.1073/pnas.1004185107.
  41. Gupta, S., Agrawal, S., and Gollapudi, S. (2013) Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans, Immun. Ageing, 10, 3, doi: 10.1186/1742-4933-10-3.
  42. Frasca, D., Diaz, A., Romero, M., and Blomberg, B. B. (2020) Leptin induces immunosenescence in human B cells, Cell. Immunol., 348, 103994, doi: 10.1016/j.cellimm.2019.103994.
  43. Chen, J., Tan, B., Karteris, E., Zervou, S., Digby, J., Hillhouse, E. W., et al. (2006) Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines, Diabetologia, 49, 1292-1302, doi: 10.1007/s00125-006-0194-7.
  44. Zhang, K., Guo, Y., Ge, Z., Zhang, Z., Da, Y., Li, W., et al. (2017) Adiponectin suppresses T helper 17 Cell differentiation and limits autoimmune CNS inflammation via the SIRT1/PPARγ/RORγt pathway, Mol. Neurobiol., 54, 4908-4920, doi: 10.1007/s12035-016-0036-7.
  45. Li, W., Geng, L., Liu, X., Gui, W., and Qi, H. (2019) Recombinant adiponectin alleviates abortion in mice by regulating Th17/Treg imbalance via p38MAPK-STAT5 pathway, Biol. Reprod., 100, 1008-1017, doi: 10.1093/biolre/ioy251.
  46. Tsang, J. Y. S., Li, D., Ho, D., Peng, J., Xu, A., Lamb, J., et al. (2011) Novel immunomodulatory effects of adiponectin on dendritic cell functions, Int. Immunopharmacol., 11, 604-609, doi: 10.1016/j.intimp.2010.11.009.
  47. Cheng, X., Folco, E. J., Shimizu, K., and Libby, P. (2012) Adiponectin induces pro-inflammatory programs in human macrophages and CD4+ T cells, J. Biol. Chem., 287, 36896-36904, doi: 10.1074/jbc.M112.409516.
  48. Tsao, T.-S., Tomas, E., Murrey, H. E., Hug, C., Lee, D. H., Ruderman, N. B., et al. (2003) Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways, J. Biol. Chem., 278, 50810-50817, doi: 10.1074/jbc.M309469200.
  49. Pang, T. T. L., and Narendran, P. (2008) The distribution of adiponectin receptors on human peripheral blood mononuclear cells, Ann. N. Y. Acad. Sci., 1150, 143-145, doi: 10.1196/annals.1447.021.
  50. Yokota, T., Meka, C. S. R., Kouro, T., Medina, K. L., Igarashi, H., Takahashi, M., et al. (2003) Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells, J. Immunol., 171, 5091-5099, doi: 10.4049/jimmunol.171.10.5091.
  51. Chimen, M., McGettrick, H. M., Apta, B., Kuravi, S. J., Yates, C. M., Kennedy, A., et al. (2015) Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease, Nat. Med., 21, 467-475, doi: 10.1038/nm.3842.
  52. Obeid, S., Wankell, M., Charrez, B., Sternberg, J., Kreuter, R., Esmaili, S., et al. (2017) Adiponectin confers protection from acute colitis and restricts a B cell immune response, J. Biol. Chem., 292, 6569-6582, doi: 10.1074/jbc.M115.712646.
  53. Che, N., Sun, X., Gu, L., Wang, X., Shi, J., Sun, Y., et al. (2021) Adiponectin enhances B-cell proliferation and differentiation via activation of Akt1/STAT3 and exacerbates collagen-induced arthritis, Front. Immunol., 12, 626310, doi: 10.3389/fimmu.2021.626310.
  54. Fukuhara, A., Matsuda, M., Nishizawa, M., Segawa, K., Tanaka, M., Kishimoto, K., et al. (2005) Visfatin: a protein secreted by visceral fat that mimics the effects of insulin, Science, 307, 426-430, doi: 10.1126/science.1097243.
  55. Samal, B., Sun, Y., Stearns, G., Xie, C., Suggs, S., and McNiece, I. (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor, Mol. Cell. Biol., 14, 1431-1437, doi: 10.1128/mcb.14.2.1431-1437.1994.
  56. Moschen, A. R., Kaser, A., Enrich, B., Mosheimer, B., Theurl, M., Niederegger, H., et al. (2007) Visfatin, an adipocytokine with proinflammatory and immunomodulating properties, J. Immunol., 178, 1748-1758, doi: 10.4049/jimmunol.178.3.1748.
  57. Craxton, A., Magaletti, D., Ryan, E. J., and Clark, E. A. (2003) Macrophage- and dendritic cell - dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF, Blood, 101, 4464-4471, doi: 10.1182/blood-2002-10-3123.
  58. Müller, N., Schulte, D. M., Hillebrand, S., Türk, K., Hampe, J., Schafmayer, C., et al. (2014) B Lymphocyte Stimulator (BLyS) is expressed in human adipocytes in vivo and is related to obesity but not to insulin resistance, PLoS One, 9, e94282, doi: 10.1371/journal.pone.0094282.
  59. Chan, C. C., Harley, I. T. W., Pfluger, P. T., Trompette, A., Stankiewicz, T. E., Allen, J. L., et al. (2021) A BAFF/APRIL axis regulates obesogenic diet-driven weight gain, Nat. Commun., 12, 2911, doi: 10.1038/s41467-021-23084-1.
  60. Kim, B., and Hyun, C.-K. (2020) B-cell-activating factor depletion ameliorates aging-dependent insulin resistance via enhancement of thermogenesis in adipose tissues, Int. J. Mol. Sci., 21, 5121, doi: 10.3390/ijms21145121.
  61. Apostolopoulos, V., de Courten, M. P. J., Stojanovska, L., Blatch, G. L., Tangalakis, K., and de Courten, B. (2016) The complex immunological and inflammatory network of adipose tissue in obesity, Mol. Nutr. Food Res., 60, 43-57, doi: 10.1002/mnfr.201500272.
  62. Biondi, G., Marrano, N., Borrelli, A., Rella, M., Palma, G., Calderoni, I., et al. (2022) Adipose tissue secretion pattern influences β-cell wellness in the transition from obesity to type 2 diabetes, Int. J. Mol. Sci., 23, 5522, doi: 10.3390/ijms23105522.
  63. Spencer, N. F., and Daynes, R. A. (1997) IL-12 directly stimulates expression of IL-10 by CD5+ B cells and IL-6 by both CD5+ and CD5- B cells: possible involvement in age-associated cytokine dysregulation, Int. Immunol., 9, 745-754, doi: 10.1093/intimm/9.5.745.
  64. Figueiró, F., Muller, L., Funk, S., Jackson, E. K., Battastini, A. M. O., and Whiteside, T. L. (2016) Phenotypic and functional characteristics of CD39high human regulatory B cells (Breg), Oncoimmunology, 5, e1082703, doi: 10.1080/2162402X.2015.1082703.
  65. Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., and Bustos, M. (2021) New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology, Nat. Rev. Gastroenterol. Hepatol., 18, 787-803, doi: 10.1038/s41575-021-00473-x.
  66. Kalliolias, G. D., and Ivashkiv, L. B. (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies, Nat. Rev. Rheumatol., 12, 49-62, doi: 10.1038/nrrheum.2015.169.
  67. Chen, X., Xun, K., Chen, L., and Wang, Y. (2009) TNF-α, a potent lipid metabolism regulator, Cell Biochem. Funct., 27, 407-416, doi: 10.1002/cbf.1596.
  68. Hotamisligil, G. S., Budavari, A., Murray, D., and Spiegelman, B. M. (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha, J. Clin. Invest., 94, 1543-1549, doi: 10.1172/JCI117495.
  69. Coppack, S. W. (2001) Pro-inflammatory cytokines and adipose tissue, Proc. Nutr. Soc., 60, 349-356, doi: 10.1079/pns2001110.
  70. Song, M., Meng, L., Liu, X., and Yang, Y. (2021) Feprazone prevents free fatty acid (FFA)-induced endothelial inflammation by mitigating the activation of the TLR4/MyD88/NF-κB pathway, ACS Omega, 6, 4850-4856, doi: 10.1021/acsomega.0c05826.
  71. Xu, Y., Wu, K., Han, S., Ding, S., Lu, G., Lin, Z., et al. (2020) Astilbin combined with lipopolysaccharide induces IL-10-producing regulatory B cells via the STAT3 signalling pathway, Biomed. Pharmacother., 129, 110450, doi: 10.1016/j.biopha.2020.110450.
  72. Wang, K., Tao, L., Su, J., Zhang, Y., Zou, B., Wang, Y., et al. (2017) TLR4 supports the expansion of FasL+CD5+CD1dhi regulatory B cells, which decreases in contact hypersensitivity, Mol. Immunol., 87, 188-199, doi: 10.1016/j.molimm.2017.04.016.
  73. McLaughlin, T., Ackerman, S. E., Shen, L., and Engleman, E. (2017) Role of innate and adaptive immunity in obesity-associated metabolic disease, J. Clin. Invest., 127, 5-13, doi: 10.1172/JCI88876.
  74. Xiao, Y., Deng, C., and Zhou, Z. (2021) The multiple roles of B lymphocytes in the onset and treatment of type 1 diabetes: interactions between B lymphocytes and T cells, J. Diabetes Res., 2021, 6581213, doi: 10.1155/2021/6581213.
  75. Fernandez, N. C., and Shinoda, K. (2022) The role of B lymphocyte subsets in adipose tissue development, metabolism, and aging, Compr. Physiol., 12, 4133-4145, doi: 10.1002/cphy.c220006.
  76. Karl, M., Hasselwander, S., Zhou, Y., Reifenberg, G., Kim, Y. O., Park, K.-S., et al. (2022) Dual roles of B lymphocytes in mouse models of diet-induced nonalcoholic fatty liver disease, Hepatology, 76, 1135-1149, doi: 10.1002/hep.32428.
  77. Kim, Y. H., Choi, B. H., Cheon, H. G., Do, M. S. (2009) B cell activation factor (BAFF) is a novel adipokine that links obesity and inflammation, Exp. Mol. Med., 41, 208-216, doi: 10.3858/emm.2009.41.3.024.
  78. Francisco, V., Pino, J., Gonzalez-Gay, M. A., Mera, A., Lago, F., Gómez, R., et al. (2018) Adipokines and inflammation: is it a question of weight? Br. J. Pharmacol., 175, 1569-1579, doi: 10.1111/bph.14181.
  79. Dludla, P. V., Nkambule, B. B., Mazibuko-Mbeje, S. E., Nyambuya, T. M., Mxinwa, V., Mokgalaboni, K., et al. (2021) Adipokines as a therapeutic target by metformin to improve metabolic function: a systematic review of randomized controlled trials, Pharmacol. Res., 163, 105219, doi: 10.1016/j.phrs.2020.105219.

Copyright (c) 2023 Russian Academy of Sciences

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies