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Leptin and adiponectin supplementation modifies mesenteric lymph node lymphocyte composition and functionality in suckling rats

  • Blanca Grases-Pintó (a1) (a2), Mar Abril-Gil (a1) (a2), Maria J. Rodríguez-Lagunas (a1) (a2), Margarida Castell (a1) (a2), Francisco J. Pérez-Cano (a1) (a2) and Àngels Franch (a1) (a2)...

At birth, when immune responses are insufficient, there begins the development of the defence capability against pathogens. Leptin and adiponectin, adipokines that are present in breast milk, have been shown to play a role in the regulation of immune responses. We report here, for the first time, the influence of in vivo adipokine supplementation on the intestinal immune system in early life. Suckling Wistar rats were daily supplemented with leptin (0·7 μg/kg per d, n 36) or adiponectin (35 μg/kg per d, n 36) during the suckling period. The lymphocyte composition, proliferation and cytokine secretion from mesenteric lymph node lymphocytes (on days 14 and 21), as well as intestinal IgA and IgM concentration (day 21), were evaluated. At day 14, leptin supplementation significantly increased the TCRαβ + cell proportion in mesenteric lymph nodes, in particular owing to an increase in the TCRαβ + CD8+ cell population. Moreover, the leptin or adiponectin supplementation promoted the early development CD8+ cells, with adiponectin being the only adipokine capable of enhancing the lymphoproliferative ability at the end of the suckling period. Although leptin decreased intestinal IgA concentration, it had a trophic effect on the intestine in early life. Supplementation of both adipokines modulated the cytokine profile during (day 14) and at the end (day 21) of the suckling period. These results suggest that leptin and adiponectin during suckling play a role in the development of mucosal immunity in early life.

Corresponding author
* Corresponding author: F. J. Pérez-Cano, fax +34 934 035 901, email:
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1. Szekeres-bartho, J (2002) Immunological relationship between the mother and the fetus . Int Rev Immunol 21, 471495.
2. Palmeira, P & Carneiro-Sampaio, M (2016) Immunology of breast milk. Rev Assoc Med Bras 62, 584593.
3. Schelonka, RL & Infante, AJ (1998) Neonatal immunology. Semin Perinatol 22, 214.
4. Pérez-Cano, FJ, Franch, À, Castellote, C, et al. (2012) The suckling rat as a model for immunonutrition studies in early life. Clin Dev Immunol 2012, 537310.
5. Levy, O (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7, 379390.
6. Wynn, JL, Scumpia, PO, Winfield, RD, et al. (2008) Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood 112, 17501758.
7. Basha, S, Surendran, N & Pichichero, M (2014) Immune responses in neonates. Expert Rev Clin Immunol 10, 11711184.
8. Chin, AM, Hill, DR, Aurora, M, et al. (2016) Morphogenesis and maturation of the embryonic and postnatal intestine. Semin Cell Dev Biol 66, 8193.
9. Pérez-Cano, FJ, Castellote, C, Marín-Gallén, S, et al. (2005) Neonatal immunoglobulin secretion and lymphocyte phenotype in rat small intestine lamina propria. Pediatr Res 58, 164169.
10. Pérez-Cano, FJ, Castellote, C, González-Castro, AM, et al. (2005) Developmental changes in intraepithelial T lymphocytes and NK cells in the small intestine of neonatal rats. Pediatr Res 58, 885891.
11. Cornes, JS (1965) Number, size, and distribution of Peyer’s patches in the human small intestine: Part I The development of Peyer’s patches. Gut 6, 225229.
12. Hanson, LA, Korotkova, M, Lundin, S, et al. (2003) The transfer of immunity from mother to child. Ann N Y Acad Sci 987, 199206.
13. Lönnerdal, B (2003) Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 77, 1537S1543S.
14. Ozarda, Y, Gunes, Y & Tuncer, GO (2012) The concentration of adiponectin in breast milk is related to maternal hormonal and inflammatory status during 6 months of lactation. Clin Chem Lab Med 50, 911917.
15. Newburg, DS, Woo, JG & Morrow, AL (2010) Characteristics and potential functions of human milk adiponectin. J Pediatr 156, Suppl. 2, S41S46.
16. Blüher, M & Mantzoros, CS (2015) From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 64, 131145.
17. Batra, A, Okur, B, Glauben, R, et al. (2010) Leptin: a critical regulator of CD4+ T-cell polarization in vitro and in vivo . Endocrinology 151, 5662.
18. Luo, Y & Liu, M (2016) Adiponectin: a versatile player of innate immunity. J Mol Cell Biol 8, 120128.
19. Wolf, AM, Wolf, D, Rumpold, H, et al. (2004) Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 323, 630635.
20. Tsatsanis, C, Zacharioudaki, V, Androulidaki, A, et al. (2005) Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem Biophys Res Commun 335, 12541263.
21. Park, PH, McMullen, MR, Huang, H, et al. (2007) Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production. J Biol Chem 282, 2169521703.
22. Picó, C, Oliver, P, Sánchez, J, et al. (2007) The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int J Obes (Lond) 31, 11991209.
23. Weyermann, M, Brenner, H & Rothenbacher, D (2007) Adipokines in human milk and risk of overweight in early childhood: a prospective cohort study. Epidemiology 18, 722729.
24. Martin, LJ, Woo, JG, Geraghty, SR, et al. (2006) Adiponectin is present in human milk and is associated with maternal factors. Am J Clin Nutr 83, 11061111.
25. Pérez-Cano, FJ, Marín-Gallén, S, Castell, M, et al. (2007) Bovine whey protein concentrate supplementation modulates maturation of immune system in suckling rats. Br J Nutr 98, Suppl. 1, S80S84.
26. Pérez-Cano, FJ, Marín-Gallén, S, Castell, M, et al. (2008) Supplementing suckling rats with whey protein concentrate modulates the immune response and ameliorates rat rotavirus-induced diarrhea. J Nutr 138, 23922398.
27. Camps-Bossacoma, M, Pérez-Cano, FJ, Franch, À, et al. (2017) Gut microbiota in a rat oral sensitization model: effect of a cocoa-enriched diet. Oxid Med Cell Longev 2017, 7417505.
28. Rigo-Adrover, M, Franch, À, Castell, M, et al. (2016) Preclinical immunomodulation by the probiotic Bifidobacterium breve M-16V in early life. PLOS ONE 11, e0166082.
29. Çatlı, G, Dündar, NO & Dündar, BN (2014) Adipokines in breast milk: an update. J Clin Res Pediatr Endocrinol 6, 192201.
30. Naylor, C & Petri, WA (2016) Leptin regulation of immune responses. Trends Mol Med 22, 8898.
31. Carbone, F, La Rocca, C & Matarese, G (2012) Immunological functions of leptin and adiponectin. Biochimie 94, 20822088.
32. Sánchez, J, Oliver, P, Miralles, O, et al. (2005) Leptin orally supplied to neonate rats is directly uptaken by the immature stomach and may regulate short-term feeding. Endocrinology 146, 25752582.
33. Uner, AG & Sulu, N (2012) In vivo effects of leptin on lymphocyte subpopulations in mice. Immunobiology 217, 882888.
34. Ahima, RS, Prabakaran, D, Mantzoros, C, et al. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250252.
35. Friedman, JM & Halaas, JL (1998) Leptin and the regulation of body weight in mammals. Nature 395, 763770.
36. Proulx, K, Richard, D & Walker, CD (2002) Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology 143, 46834692.
37. Bruun, JM, Lihn, AS, Verdich, C, et al. (2003) Regulation of adiponectin by adipose tissue-derived cytokines : in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285, E527E533.
38. Meilian, L & Feng, L (2014) Regulation of adiponectin multimerization, signaling and function. Best Pract Res Clin Endocrinol Metab 28, 2531.
39. Wang, ZV & Scherer, PE (2016) Adiponectin, the past two decades. J Mol Cell Biol 8, 93100.
40. Savino, F, Lupica, MM, Benetti, S, et al. (2012) Adiponectin in breast milk: relation to serum adiponectin concentration in lactating mothers and their infants. Acta Paediatr Int J Paediatr 101, 10581062.
41. Massot-Cladera, M, Franch, À, Pérez-Cano, FJ, et al. (2016) Cocoa and cocoa fibre differentially modulate IgA and IgM production at mucosal sites. Br J Nutr 115, 15391546.
42. Martin, R, Nauta, AJ, Ben Amor, K, et al. (2010) Early life: gut microbiota and immune development in infancy. Benef Microbes 1, 367382.
43. Adkins, B (2007) Heterogeneity in the CD4 T cell compartment and the variability of neonatal immune responsiveness. Curr Immunol Rev 3, 151159.
44. Procaccini, C, De Rosa, V, Galgani, M, et al. (2013) Role of adipokines signaling in the modulation of T cells function. Front Immunol 4, 332.
45. Oral, EA, Javor, ED, Ding, L, et al. (2006) Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy. J Clin Endocrinol Metab 91, 621628.
46. Howard, JK, Lord, GM, Matarese, G, et al. (1999) Leptin protects mice from starvation induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 104, 10511059.
47. Fernández-Riejos, P, Najib, S, Santos-Alvarez, J, et al. (2010) Role of leptin in the activation of immune cells. Mediators Inflamm 2010, 568343.
48. Fujita, Y, Murakami, M, Ogawa, Y, et al. (2002) Leptin inhibits stress-induced apoptosis of T lymphocytes. Clin Exp Immunol 128, 2126.
49. Wilk, S, Scheibenbogen, C, Bauer, S, et al. (2011) Adiponectin is a negative regulator of antigen-activated T cells. Eur J Immunol 41, 23232332.
50. Camps-Bossacoma, M, Abril-Gil, M, Saldaña-Ruiz, S, et al. (2016) Cocoa diet prevents antibody synthesis and modifies lymph node composition and functionality in a rat oral sensitization model. Nutrients 8, 242.
51. Abella, V, Scotece, M, Conde, J, et al. (2017) Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 13, 100109.
52. Dagogo-Jack, S (editor) (2015) Leptin: Regulation and Clinical Applications. New York: Springer International Publishing.
53. Wrann, CD, Laue, T, Hübner, L, et al. (2012) Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions. Am J Physiol Endocrinol Metab 302, E108E116.
54. Stofkova, A (2009) Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity. Endocr Regul 43, 157168.
55. FitzGerald, AJ, Mandir, N & Goodlad, RA (2005) Leptin, cell proliferation and crypt fission in the gastrointestinal tract of intravenously fed rats. Cell Prolif 38, 2533.
56. Fraser, DA, Thoen, J, Reseland, JE, et al. (1999) Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin Rheumatol 18, 394401.
57. Okamoto, Y, Kihara, S, Ouchi, N, et al. (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106, 27672770.
58. Maeda, N, Shimomura, I, Kishida, K, et al. (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8, 731737.
59. Kumada, M, Kihara, S, Ouchi, N, et al. (2004) Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109, 20462049.
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