Advertisement

Journal of Molecular Medicine

, Volume 82, Issue 1, pp 4–11 | Cite as

Unraveling the multiple roles of leptin in inflammation and autoimmunity

  • Antonio La Cava
  • Carlo Alviggi
  • Giuseppe Matarese
Review

Abstract

Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and immune homeostasis. Leptin links nutritional status and proinflammatory T helper 1 immune responses, and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. This review focuses on the multiple roles of leptin in chronic inflammation and autoimmunity and suggests new possible therapeutic implications for leptin modulators.

Keywords

Leptin Autoimmunity Inflammation T cells 

Abbreviations

EAE

Experimental autoimmune encephalomyelitis

IFN

Interferon

IL

Interleukin

Th

T helper

TNF

Tumor necrosis factor

Notes

Acknowledgements

This work is partly supported by Fondazione Italiana Sclerosi Multipla and Comitato Trenta Ore per la Vita (Mediaset). A.L.C. is supported by the Arthritis National Research Foundation, the Lupus Foundation of America, and the California Community Foundation. This work is dedicated to the memory of Prof. Antonino Di Tuoro.

References

  1. 1.
    Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770PubMedGoogle Scholar
  2. 2.
    Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW (1997) Crystal structure of the obese protein leptin-E100. Nature 387:206–208Google Scholar
  3. 3.
    Tartaglia LA (1997) The leptin receptor. J Biol Chem 272:6093–6070PubMedGoogle Scholar
  4. 4.
    Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS (1998) Leptin regulates proinflammatory immune responses. FASEB J 12:57–63PubMedGoogle Scholar
  5. 5.
    Matarese G (2000) Leptin and the immune system: how nutritional status influences the immune response. Eur Cytokine Netw 11:7–14PubMedGoogle Scholar
  6. 6.
    Flier JS (1998) Lowered leptin slims immune response. Nat Med 10:1124–1125CrossRefGoogle Scholar
  7. 7.
    Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252Google Scholar
  8. 8.
    Chan JL, Heist C, DePaoli A, Veldhuis JD, Mantzoros CS (2003) The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 111:1409–1421CrossRefPubMedGoogle Scholar
  9. 9.
    Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ (1998) The stomach is a source of leptin. Nature 395:790–792Google Scholar
  10. 10.
    Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901Google Scholar
  11. 11.
    Chandra RK (1980) Cell-mediated immunity in genetically obese (C57BL/6\J ob/ob) mice. Am J Clin Nutr 33:13–20PubMedGoogle Scholar
  12. 12.
    Mandel MA, Mahmoud AA (1978) Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J Immunol 120:1375–1380PubMedGoogle Scholar
  13. 13.
    Fernandes G, Handwerger BS, Yunis EJ, Brown DM (1978) Immune response in the mutant diabetic C57BL/Ks-dt+ mouse. Discrepancies between in vitro and in vivo immunological assays. J Clin Invest 61:243–249PubMedGoogle Scholar
  14. 14.
    Ozata M, Ozdemir IC, Licinio J (1998) Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicates new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84:3686–3690Google Scholar
  15. 15.
    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–400Google Scholar
  16. 16.
    Lichtman AH, Abbas AK (1997) T-cell subsets: recruiting the right kind of help. Curr Biol 7:R242–44PubMedGoogle Scholar
  17. 17.
    Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA, Lechler RI, Bloom SR (1999) Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 104:1051–1059PubMedGoogle Scholar
  18. 18.
    Moret Y, Schmid-Hempel P (2000) Survival for immunity: the price of immune system activation for bumblebee workers. Science 290:1166–1168PubMedGoogle Scholar
  19. 19.
    Lord GM, Matarese G, Howard JK, Lechler RI (2001) The bioenergetics of the immune system. Science 292:855–856CrossRefPubMedGoogle Scholar
  20. 20.
    Mancuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW, Huffnagle GB (2002) Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol 168:4018–4024PubMedGoogle Scholar
  21. 21.
    Gualillo O, Eiras S, Lago F, Dieguez C, Casanueva FF (2000) Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci 67:2433–2441CrossRefPubMedGoogle Scholar
  22. 22.
    Barbier M, Attoub S, Joubert M, Bado A, Laboisse C, Cherbut C, Galmiche JP (2001) Proinflammatory role of leptin in experimental colitis in rats benefit of cholecystokinin-B antagonist and beta3-agonist. Life Sci 69:567–580CrossRefPubMedGoogle Scholar
  23. 23.
    Sanna V, Di Giacomo A, La Cava A, Lechler RI, Fontana S, Zappacosta S, Matarese G (2003) Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest 111:241–250CrossRefPubMedGoogle Scholar
  24. 24.
    Landman RE, Puder JJ, Xiao E, Freda PU, Ferin M, Wardlaw SL (2003) Endotoxin stimulates leptin in the human and nonhuman primate. J Clin Endocrinol Metab 88:1285–1291CrossRefPubMedGoogle Scholar
  25. 25.
    Matarese G, Alviggi C, Sanna V, Howard JK, Lord GM, Carravetta C, Fontana S, Lechler RI, Bloom SR, De Placido G (2000) Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis. J Clin Endocrinol Metab 85:2483–2487PubMedGoogle Scholar
  26. 26.
    Schols AM, Creutzberg EC, Buurman WA, Campfield LA, Saris WH, Wouters EF (1999) Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:1220–1226PubMedGoogle Scholar
  27. 27.
    Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G (2000) Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. Proc Natl Acad Sci U S A 97:2367–2372CrossRefPubMedGoogle Scholar
  28. 28.
    Oral, E, Arici A (1997) Pathogenesis of endometriosis. Obstet Gynecol Clin North Am 24:219–233PubMedGoogle Scholar
  29. 29.
    Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, Jang Y, Cho SY, Kim HS (2001) Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med 33:95–102PubMedGoogle Scholar
  30. 30.
    Shimabukuro M, Wang MY, Zhou YT, Newgard CB, Unger RH (1998) Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci U S A 95:9558–9561CrossRefPubMedGoogle Scholar
  31. 31.
    Vinatier D, Dufour P (1997) Is endometriosis an immunological disease? Contracept Fertil Sex 25:179–191PubMedGoogle Scholar
  32. 32.
    Gonzalez RR, Caballero-Campo P, Jasper M, Mercader A, Devoto L, Pellicer A, Simon C (2000) Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab 85:4883–4888PubMedGoogle Scholar
  33. 33.
    Steinman L (1999) Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 24:511–514PubMedGoogle Scholar
  34. 34.
    Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, Zappacosta S, Fontana S (2001) Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916PubMedGoogle Scholar
  35. 35.
    Matarese G, Sanna V, Lechler RI, Sarvetnick N, Fontana S, Zappacosta S, La Cava A (2002) Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes 51:1356–1361PubMedGoogle Scholar
  36. 36.
    Busso N, So A, Chobaz-Peclat V, Morard C, Martinez-Soria E, Talabot-Ayer D, Gabay C (2002) Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 168:875–882PubMedGoogle Scholar
  37. 37.
    Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 122:2011–2025PubMedGoogle Scholar
  38. 38.
    Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O’Rahilly S (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093–1103CrossRefPubMedGoogle Scholar
  39. 39.
    Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour B (2003) Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab 88:109–116CrossRefPubMedGoogle Scholar
  40. 40.
    Allende LM, Corell A, Manzanares J, Madruga D, Marcos A, Madrono A, Lopez-Goyanes A, Garcia-Perez MA, Moreno JM, Rodrigo M, Sanz F, Arnaiz-Villena A (1998) Immunodeficiency associated with anorexia nervosa is secondary and improves after refeeding. Immunology 94:543–551CrossRefPubMedGoogle Scholar
  41. 41.
    Ballinger A, Kelly P, Hallyburton E, Besser R, Farthing M (1998) Plasma leptin in chronic inflammatory bowel disease and HIV: implications for the pathogenesis of anorexia and weight loss. Clin Sci (Colch) 94:479–483Google Scholar
  42. 42.
    Grunfeld C, Pang M, Shigenaga JK, Jensen P, Lallone R, Friedman J, Feingold KR (1996) Serum leptin levels in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 81:4342–4346PubMedGoogle Scholar
  43. 43.
    Matarese G, Castelli-Gattinara G, Cancrini C, Bernardi S, Romiti ML, Savarese C, Di Giacomo A, Rossi P, Racioppi L (2002) Serum leptin and CD4+ T lymphocytes in HIV+ children during highly active antiretroviral therapy. Clin Endocrinol (Oxf) 57:643–646Google Scholar
  44. 44.
    Reseland JE, Haugen F, Hollung K, Solvoll K, Halvorsen B, Brude IR, Nenseter MS, Christiansen EN, Drevon CA (2001) Reduction of leptin gene expression by dietary polyunsaturated fatty acids. J Lipid Res 42:743–750PubMedGoogle Scholar
  45. 45.
    Mantzoros CS, Prasad AS, Beck FW, Grabowski S, Kaplan J, Adair C, Brewer GJ (1998) Zinc may regulate serum leptin concentrations in humans. J Am Coll Nutr 17:270–275PubMedGoogle Scholar
  46. 46.
    Fraser DA, Thoen J, Reseland JE, Forre O, Kjeldsen-Kragh J (1999) Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin Rheumatol 18:394–401CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Antonio La Cava
    • 1
  • Carlo Alviggi
    • 2
  • Giuseppe Matarese
    • 3
  1. 1.Department of MedicineUniversity of California Los AngelesLos AngelesUSA
  2. 2.Dipartimento di Scienze Ostetriche, Ginecologiche, Urologiche e Medicina della RiproduzioneUniversità di Napoli Federico IINaplesItaly
  3. 3.Gruppo di ImmunoEndocrinologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, c/o Dipartimento di Biologia e Patologia Cellulare e MolecolareUniversità di Napoli Federico IINaplesItaly

Personalised recommendations