- Email: [email protected]
Leptin, from fat to inflammation: old questions and new insights
FEBS 29055
FEBS Letters 579 (2005) 295–301
Minireview
Leptin, from fat to inflammation: old questions and new insights Miguel Oteroa, Rocı´o Lagoa, Francisca Lagob, Felipe F. Casanuevac, Carlos Dieguezd, Juan Jesu´s Go´mez-Reinoe, Oreste Gualilloa,* a
Santiago University Clinical Hospital, Research Laboratory 4 (NEIRID LAB, Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago de Compostela, Spain b Santiago University Clinical Hospital, Research Laboratory 1 (Molecular and Cellular Cardiology), Santiago de Compostela, Spain c Molecular Endocrinology Section, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain d Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain e Rheumatology Division, Department of Medicine, Santiago University Clinical Hospital, University of Santiago de Compostela, Spain Received 11 August 2004; revised 9 October 2004; accepted 4 November 2004 Available online 8 December 2004 Edited by Veli-Pekka Lehto
Abstract Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses. Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: Leptin; Imflammation
1. A brief introduction Until recently, fat was considered to serve prevalently as the triglyceride reservoir of the body and was relegated to a pas* Corresponding author. Fax: +34 981 951068. E-mail address: [email protected] (O. Gualillo).
sive endocrine role. The fact that adipose tissue was identified as the major site for metabolism of sex steroid and then the discovery of the leptin, as well successively of other adipocytokines (adiponectin, resistin), changed completely this traditional view. Most of the products secreted by adipose tissue play a lead role in inflammation and immune response, namely fat cells produce interleukin-6, tumor necrosis factor a and many other cytokines and hormones including leptin. This review focuses prevalently on the complex relationships existing among leptin, inflammation processes and immune response, trying to explore the paradigms that have shaped the past decadeÕs research and what these findings forecast for the future.
2. Leptin biology overlook Leptin is a peptide hormone that is produced predominantly by white adipose cells [1,2]. The mature protein, that is encoded by the obese (ob) gene localized into human and mouse 7 and 6 chromosomes, respectively, is a 16 kDa non-glycosylated protein. Structurally, it belongs to the type I cytokine superfamily and is characterized by a long chain four-helical bundle structure, such as growth hormone, prolactin, IL-3, and others. Circulating leptin levels are proportional to adipose tissue mass. Thus, leptin levels can be considered as a signal to the body of its energy reserves. Although elevated leptin levels are present in obesity, it is likely that the physiological importance of leptin is that low levels signal starvation [3]. 2.1. Modulation of leptin expression Leptin gene expression is regulated by several factors but mainly by food intake and hormones. For example, insulin stimulates leptin secretion during feeding and a decrease of insulin levels precedes a fall in leptin concentrations during starvation in humans [4–6]. An inverse relationship between leptin and glucocorticoids has been observed, although glucocorticoids may mediate a synergic action with insulin on cultured adipocytes [7–9]. Leptin synthesis increases in response to acute infection, sepsis and secretion of inflammatory mediators as IL-1, TNF-a and LIF [10–12]. Furthermore, the expression of this hormone is inhibited by testosterone, whereas it is increased by ovarian sex steroids [13–15].
0014-5793/$22.00 Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2004.11.024
296
2.2. Leptin biological actions Central nervous system, namely hypothalamic nuclei, is the target where leptin exerts most of its effects on energy metabolism. Leptin decreases food intake, increases energy expenditure and decreases metabolic efficiency. Leptin has been shown to influence a wide spectrum of biological functions, such as lipid and glucose metabolism, synthesis of glucocorticoids, insulin, CD4+ T lymphocyte proliferation, cytokine secretion, phagocytosis and synaptic transmission [16–19]. In addition, it regulates the hypothalamic–pituitary–adrenal axis [20–22], maturation of the reproductive system [23–26], hematopoiesis [27,28], angiogenesis [29,30] and fetal development [31,32]. 2.3. Leptin receptors Leptin receptor (Ob-R) is encoded by the diabetes (db) gene that has been cloned from mouse choroid plexus [33,34]. The Ob-R mRNA is alternatively spliced giving rise to six different spliced forms of the receptor known as Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re and Ob-Rf [35,36]. Ob-R is a member of the class I cytokine receptor superfamily, which includes receptors for IL-6, LIF, CNTF, OSM, G-CSF and gp 130 with predominantly hematopoietic expression [37,38]. These receptors are membrane-spanning glycoproteins. In the extracellular region, they present fibronectin type III domains and a shared 200-amino acid module, that contains four conserved cysteine residues and the membrane proximal region WSXWS (trp-serX-trp-ser) motif. The different mRNA spliced forms encode for Ob-R with different length cytoplasmic domains: Ob-Rb, also known as the long receptor isoform, has 302 cytoplasmic residues containing the activation and signal transduction motifs; the other forms with a 34-amino acid residue cytoplasmic domain and the soluble one (Ob-Re) lacks some or all of these motifs. The short forms of leptin receptor are expressed in choroid plexus, kidney, gonads, liver, lung and vascular endothelium, where they mediate leptin transport into the brain, degradation and clearance [39,40]. Ob-Rb is primarily expressed at high levels in the hypothalamus, especially in the arcuate, dorsomedial, ventromedial and lateral hypothalamic nuclei, a crucial area that secrete neuropeptides and neurotransmitters involved in the regulation of appetite and body weight. Furthermore, the long isoform is expressed in murine and human fetal liver, jejunal epithelium, pancreatic b cells, ovarian follicular cells, vascular endothelial cells, CD34+ hematopoietic bone marrow precursors, and T lymphocytes [17,27,29,30]. 2.4. Leptin receptor signal transduction: the JAK2/STAT pathway Ligand binding to Ob-Rb activates Janus kinases (JAK2) and signal transducers and activators of transcription (STAT) proteins as occurs with the other members of the class I cytokine receptor family [41,42]. All the four membrane-bound leptin receptors contain in the cytoplasmic tail a box 1 motif, strongly conserved within most members of this receptor family, whereas box 2 and 3 motifs are found only in the long isoform. Domains 1 and 2 are involved in the interaction and activation of JAK2 tyrosine kinase that phosphorylates and activates members of the STAT family of transcription factors, such as STAT1, STAT3 and STAT5. The activation of STAT3 has been observed in vivo in the hypothalamus and requires a box 3 motif in the receptor intracellular domain [43,44]. Acti-
M. Otero et al. / FEBS Letters 579 (2005) 295–301
vated JAK2 phosphorylates tyrosine residues in the intracellular domain of Ob-Rb, providing binding motifs for SHP-2 and STAT proteins [45–47]. These transcription factors, after tyrosine-phosphorylation in response to JAK activation, translocate to the nucleus, where they activate gene transcription. In particular, leptin modulates the expression of STAT3dependent target genes in hypothalamic neurons expressing Ob-Rb, which include c-fos, c-jun, suppressor of cytokine signaling-3 and genes encoding neuropeptides such as neuropeptide Y, agouti-related peptide, cocaine- and amphetamineregulated transcript, proopiomelanocortin and thyrotropinreleasing hormone [46]. 2.5. Leptin receptor alternative signaling pathways In vitro and in vivo studies showed that Ob-Rb stimulates tyrosine phosphorylation of IRS-1, PI 3-kinase activity and SHP-2-dependent ERK1/2 activation [47,48]. On the other hand, the short form Ob-Ra, which is highly expressed in the microvessels of the blood–brain barrier, has the capacity in vitro to activate JAK2, ERK2 and to phosphorylate IRS-1 in a leptin-dose manner, but is not able to activate STAT3 and downstream target c-fos gene transcription. Furthermore, it has been shown that leptin induces a marked phosphorylation of p38 MAP kinase in human peripheral blood mononuclear cells [49]. Very recently, Gualillo et al. [50] demonstrated that leptin is able to induce intracellular signal transduction pathways alternative to JAK/STAT by inducing tyrosine phosphorylation of the SH(2) containing protein SHC. These studies, carried out on a human embryonic cell line (HEK 293) transfected with the cDNA encoding for the long form of the leptin receptor and stably expressing the receptor itself, showed that upon tyrosine phosphorylation, SHC associated with the adaptor protein, Grb-2. The formation of this complex may directly link tyrosine phosphorylation events to Ras activation and may be a critical step in proliferation and/or differentiation of cells, indicating that leptin receptor, after binding the ligand, activates several pathways for signal transduction that might lead to mitogenic effect. Very recent data have demonstrated the critical role of specific tyrosine residues conserved in the cytoplasmic domains namely those situated at positions Y985, Y1077 and Y1138 of the murine receptor. For instance, the Y1138 residue seems likely to be a typical STAT3 docking site and the sharp role of this residue was further confirmed by knock-in mice expressing a Y1138S mutated receptor. This mutation induces a deep obesity in the knocked-in mice and suggests an essential role for the Y1138, and thus also for STAT3, in leptin-regulated energy homeostasis. However, and intriguingly, infertility and other defects naturally observed in the db/db mouse were not found in the Y1138S knock-in mouse, so implying a STAT3-independent leptin receptor signaling transduction pathway [51,52].
3. Leptin: a novel immunomodulator Several studies have demonstrated that leptin circulating levels increase during infection and inflammation, suggesting that leptin is part of the immune response and host defense mechanisms. Leptin levels are acutely increased by many acute phase factors, such as TNF, IL-1 and IL-6, and during bacterial infection, or lipopolysaccharide challenge [53]. Further-
M. Otero et al. / FEBS Letters 579 (2005) 295–301
more, leptin levels are elevated during carrageenan induced rat paw edema and carrageenan-induced pleurisy [12]. Leptin, per se, acts on monocytes/macrophages by inducing eicosanoids synthesis, nitric oxide and several pro-inflammatory cytokines [54,55]. In addition, leptin potentiates IFN-c-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1 [56]. Moreover, leptin induces chemotaxis of neutrophils and the release of oxygen radicals [57,58]. Leptin also affects natural killer (NK)-cell development and activation both in vitro and in vivo [59,60]. As NK cells express OBRb and db/db mice have a deficit of NK cells resulting from abnormal NK-cell development, it is reasonable that leptin might influence the development/maintenance of a normal peripheral NK-cell pool. Indeed, an important role of OBRb in NK-cell physiology is indicated by the ability of OBRb to influence NK-cell cytotoxicity through direct activation of signal transducer and activator of transcription 3. Finally, it has recently been shown that leptin stimulates the production of growth hormone by peripheral-blood mononuclear cells through protein kinase C (PKC)- and nitric oxide-dependent pathways [61]. This effect of leptin on the production of growth hormone might be important in immune homeostasis, given the fact that this cytokine-like hormone has marked influences on immune responses by controlling the survival and proliferation of immune cells. Leptin has been demonstrated to also modulate adaptive immune response. This is divided classically into T helper 1 and 2 immune responses on the basis of the cytokine pattern produced. T helper 1 lymphocytes produce mainly pro-inflammatory cytokines that are necessary for macrophage activation and cell-mediated response, whereas T helper 2 lymphocytes secrete modulatory and anti-inflammatory peptides that are important factors for the activation of B cells and basophils. The role of leptin in adaptive immune response was recently and extensively reviewed by La Cava and Matarese [62], and here we briefly summarize some of the aspects previously exposed. Recent articles reported that leptin deficiency is responsible for the immunosuppression and thymic atrophy observed during acute starvation and reduced caloric intake [17]. The impairment of the immune response is associated with a dramatic fall in serum leptin and is reverted by exogenous leptin in rodents. Leptin in mice is necessary for an effective cell-mediated immunity and the CD4+ T lymphocytes function is suboptimal in the absence of leptin as observed in the ob/ob mice [17]. In addition, there are several evidences that leptin participates in the maintenance of thymic maturation of double positive CD4+/CD8+ cells and prevents glucocorticoids-induced apoptosis in thymocytes, since both leptin deficient mice as well as starved animals show a reduction in the thymus cortex and exogenous leptin administration is able to restore normal thymic function, increasing the number of CD4+/CD8+ T lymphocytes and reducing thymic apoptosis [63]. 3.1. Leptin and autoimmune diseases Leptin likely has an important role in autoimmune states such as those observed in inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Inflammatory bowel disease is often associated with a marked weight loss compared with non-affected individuals. In a specific intestinal inflammation model, the trinitrobenzene sulphonic acid colitis induced rats, it has been shown that plasma leptin levels were elevated, correlated with the degree of
297
inflammation, and associated with anorexia [64]. In addition, in the acute stage of ulcerative colitis, increased serum leptin levels have been found in adult male patients, suggesting that leptin levels may contribute to anorexia and weight loss [65]; furthermore, in inflamed colonic epithelial cells, leptin is expressed and released into the intestinal lumen [66]. Very recently, a key role for intestinal leptin in a immune experimental model of mice chronic intestinal inflammation has been demonstrated. Leptin actions in this model appear to be mediated by leptin receptor transduction pathway on Th-1 lymphocytes [67]. In experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis, the onset of the disease is preceded by an augment of serum leptin concentrations [68]. Noteworthy, acute starvation, which reduces serum leptin levels, delays disease onset and attenuates the symptoms. In addition, leptin-deficient ob/ob mice are resistant against encephalomyelitis. This resistance is abolished by administration of leptin, which is accompanied by a switch from a Th2 to Th1 pattern of cytokine release [69]. In type 1 diabetes, the pancreatic b-cells are destroyed by immune-inflammatory processes. The non-obese diabetic (NOD) mouse is one of the best animal model for type 1 diabetes. In NOD susceptible female mice, increased serum level of leptin precedes the onset of diabetes, whereas injection of leptin speed up the autoimmune destruction of the pancreatic b-cells and increases the IFN-c production in peripheral T-cells, arguing that leptin promotes the development of type 1 diabetes through Th1 responses [70].
3.2. Leptin and rheumatoid arthritis Leptin likely plays a major role in the pathogenesis of rheumatoid arthritis. In experimental antigen-induced arthritis, both ob/ob and db/db mice develop less severe arthritis in comparison with wild type mice and display decreased interleukin1b and tumor necrosis factor-a in the knee synovial fluid. In addition, ob/ob mice display a decreased antigen-specific T-cell proliferative response, with a lower interferon-c and a higher IL-10 secretion [71]. The increased leptin production in RA patients further argues for a role of leptin in the pathogenesis of RA. In patients with rheumatoid arthritis, it was reported that fasting leads to an improvement of different clinical and biological measures of disease activity, which was associated with a marked decrease in serum leptin and a shift towards Th2 cytokine production [72]. These features, resembling those previously depicted in ob/ob mice, suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans through the induction of Th1 responses. Bokarewa et al. [73] reported increased plasma levels of leptin in 76 patients with RA as compared with healthy controls. In this work, it has also been observed that circulating plasma concentrations of leptin were significantly higher than leptin levels in matched synovial fluid samples and that the difference between plasma and synovial fluid was particularly pronounced in non-erosive arthritis. So, these authors concluded that intra-articular leptin may exert a protective effect against the destructive course of RA. Unfortunately, these data were affected by several problems that significantly limit the interpretation of their results [74]. At joint cartilage level, it has been demonstrated that chondrocytes express leptin and its cognate long form receptor
298
M. Otero et al. / FEBS Letters 579 (2005) 295–301
Fig. 1. Schematic illustration of the pleiotropic effects of leptin at central level and in the periphery with particular attention to immune system and inflammatory response in chondrocytes.
[75,76]. Furthermore, our group has demonstrated a direct effect of leptin on chondrocytes. Actually, leptin has a synergistic effect with IFN-c on nitric oxide synthase type II induction in cultured chondrocytes [77]. Nitric oxide is a gaseous mediator, induced by a wide range of pro-inflammatory cytokines, that causes most of the inflammatory alterations on cartilage including chondrocytes phenotype loss, chondrocytes apoptosis and metalloproteases activation [78]. Therefore, leptin likely acts a typical pro-inflammatory cytokine because of its synergistic action with IFN-c on nitric oxide synthase type II (Fig. 1). Even if some data suggested a protective effect of leptin in chondrocytes [79], our results pointed on a detrimental effect on chondrocytes. To further confirm a pro-inflammatory role of leptin in cartilage, recent data obtained by our group reported a synergistic effect of leptin also with IL-1, probably the most relevant cytokine playing in inflammatory diseases such as osteoarthritis, on nitric oxide synthase type II synthesis and activity in cultured chondrocytes by a signaling pathway that involves JAK2 kinase, PI-3 kinase, MEK-1 and p38 kinase [80]. These data confirm that leptin is a pro-inflammatory cytokine, and suggests that it could be the link between obesity and inflammatory conditions, particularly those related with alterations of cartilage metabolism.
4. Concluding remarks and future perspectives Since the discovery of leptin in 1994, the volume of literature on leptin biology is impressive. Although an endless series of relevant works have been carried out in the last decade to clarify the biologic role of leptin, many cellular and molecular aspects of this adipokine in immune response and inflammatory processes remain elusive. Leptin interactions with inflamma-
tion and immune system are similar to a dynamic puzzle, but where they fit the puzzle is still unclear. Nonetheless, particularly because of the close link between nutritional status and immunity and leptin modulation by food intake, this adipokine could be considered as a new potential immunological therapeutic target in conditions where leptin is thought to promote inflammatory or autoimmune diseases. For instance, one could suggest that the stress responses of acute starvation could be beneficial in some autoimmune conditions in which leptin promotes chronic inflammation. However, the hypoleptinaemia during starvation would be a potential mechanism for increased susceptibility to infection and decreased T cell response secondary to malnutrition. One potential strategy, that at first sight appears viable to counteract undesired leptin action in inflammatory and autoimmune diseases, is the possibility to use a soluble receptor, able to assure high affinity leptin binding thereby controlling the amount of bioavailable leptin. A comparable strategy was recently introduced in the clinical practice to antagonize the detrimental effects of tumor necrosis factor in rheumatoid arthritis. Other potential therapeutic interventions to antagonize leptin can be achieved by the use of monoclonal humanized antibodies or by leptin mutants with antagonistic properties which should be able to bind the leptin receptor complex without activating it [81]. However, due to the fact that leptin investigations were initially focused on weight regulation, and considering that major leptin effect on food intake and energy expenditure occurs at the hypothalamic level and that all the above mentioned molecules do not cross the blood brain barrier, only little care has been given to the development of a protein based anti-leptin therapy. Nonetheless, based on the recent observations supporting a major role of leptin in immunity, and considering that most of the effects on the immune system and inflammatory response are mediated directly
M. Otero et al. / FEBS Letters 579 (2005) 295–301
by receptors on peripheral target cells, it should be auspicious that the development of such a molecule should be boosted as a promising therapeutic intervention for inflammatory degenerative diseases such as rheumatoid arthritis, osteoarthritis and others. In conclusion, there is an increasing evidence that leptin, besides its central effects on food intake and energy expenditure, is involved (per se or by synergistic action with other cytokines) in the pathogenesis of inflammatory and autoimmune diseases. The evidence that leptin signaling deficiency impairs humoral and cellular immune responses, and attenuates experimental inflammation models, supports the notions that a strategy focused on the block of leptin activity on peripheral cells might have intriguing therapeutic benefits.
299
[14]
[15]
[16] [17]
Acknowledgements: We thank Dr. G. Matarese for his helpful advices and for his continued support. It is reasonable that not all published data were discussed in this minireview. So, we really apologize to those whose work was not mentioned. Some of the research described in this review has been supported by Spanish Ministry of Health, Fondo de Investigacio´n Sanitaria, Instituto de Salud Carlos III (FIS 01/3137, PI 020431 and G03/152), and Xunta de Galicia. Oreste Gualillo and Francisca Lago are recipients of a research contract co-funded by SERGAS and Instituto de Salud Carlos III (Exp 00/3051, 99/3040).
References [1] Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J.M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432. [2] Ahima, R.S. and Flier, J.S. (2000) Leptin. Annu. Rev. Physiol. 62, 413–437. [3] Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E. and Flier, J.S. (1996) Role of leptin in the neuroendocrine response to fasting. Nature (London) 382, 250–252. [4] Kolaczynski, J.W., Nyce, M.R., Considine, R.V., Boden, G., Nolan, J.J., Henry, R., Mudaliar, S.R., Olefsky, J. and Caro, J.F. (1996) Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 45, 699–701. [5] Boden, G., Chen, X., Kolaczynski, J.W. and Polansky, M. (1997) Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J. Clin. Invest. 100, 1107–1113. [6] Segal, K.R., Landt, M. and Klein, S. (1996) Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45, 988–991. [7] Zakrzewska, K.E., Cusin, I., Sainsbury, A., Rohner-Jeanrenaud, F. and Jeanrenaud, B. (1997) Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. Diabetes 46, 717–719. [8] De Vos, P., Saladin, R., Auwerx, J. and Staels, B. (1995) Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J. Bio. Chem. 270, 15958–15961. [9] Elimam, A., Knutsson, U., Bronegard, M., Stierna, P., Albertsson-Wikland, K. and Marcus, C. (1998) Variations in glucocorticoid levels within the physiological range affect plasma leptin levels. Eur. J. Endocrinol. 139, 615–620. [10] Faggioni, R., Fantuzzi, G., Fuller, J., Dinarello, C.A., Feingold, K.R. and Grunfeld, C. (1998) IL-1 beta mediates leptin induction during inflammation. J. Am. J. Physiol. 274, R204–R208. [11] Sarraf, P., Frederich, R.C., Turner, E.M., Ma, G., Jaskowiak, N.T., Rivet 3rd, D.J., Flier, J.S., Lowell, B.B., Fraker, D.L. and Alexander, H.R. (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J. Exp. Med. 185, 171–175. [12] Gualillo, O., Eiras, S., Lago, F., Dieguez, C. and Casanueva, F.F. (2000) Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci. 67 (20), 2433–2441. [13] Mantzoros, C.S., Moschos, S., Avramopoulos, I., Kaklamani, V., Liolios, A., Doulgerakis, D.E., Griveas, I., Katsilambros, N. and
[18]
[19] [20] [21]
[22]
[23] [24] [25]
[26] [27] [28]
[29]
[30] [31] [32]
Flier, J.S. (1997) Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J. Clin. Endocrinol. Metab. 82, 3408–3413. Blum, W.F., Englaro, P., Hatsch, S., Juul, A., Hertel, N.T., Muller, J., Skakkebaek, N.E., Heiman, M.L., Birkett, M., Attanasio, A.M., Kiess, W. and Rascher, W. (1997) Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. Clin. Endocrinol. Metab. 82, 2904–2910. Castracane, V.D., Kraemer, R.R., Franken, M.A., Kraemer, G.R. and Gimpel, T. (1998) Serum leptin concentration in women: effect of age, obesity, and estrogen administration. Fertil. Steril. 70, 472–477. Unger, R.H., Zhou, Y.T. and Orci, L. (1999) Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc. Natl. Acad. Sci. USA 96, 2327–2332. Lord, G.M., Matarese, G., Howard, J.K., Baker, R.J., Bloom, S.R. and Lechler, R.I. (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901. Gainsford, T., Willson, T.A., Metcalf, D., Handman, E., McFarlane, C., Ng, A., Nicola, N.A., Alexander, W.S. and Hilton, D.J. (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc. Natl. Acad. Sci. USA 93, 14564–14568. Haynes, W.G., Sivitz, W.J., Morgan, D.A., Walsh, S.A. and Mark, A.L. (1997) Sympathetic and cardiorenal actions of leptin. Hypertension 30, 619–623. Yu, W.H., Kimura, M., Walczewska, A., Karanth, S. and McCann, S.M. (1997) Role of leptin in hypothalamic–pituitary function. Proc. Natl. Acad. Sci. USA 94, 1023–1028. Bornstein, S.R., Uhlmann, K., Haidan, A., Ehrhart-Bornstein, M. and Scherbaum, W.A. (1997) Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 46, 1235–1238. Heiman, M.L., Ahima, R.S., Craft, L.S., Schoner, B., Stephens, T.W. and Flier, J.S. (1997) Leptin inhibition of the hypothalamic– pituitary–adrenal axis in response to stress. Endocrinology 138, 3859–3863. Strobel, A., Issad, T., Camoin, L., Ozata, M. and Strosberg, A.D. (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet 18, 213. Chehab, F.F., Lim, M.E. and Lu, R. (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 12, 318–320. Barash, I.A., Cheung, C.C., Weigle, D.S., Ren, H., Kabigting, E.B., Kuijper, J.L., Clifton, D.K. and Steiner, R.A. (1997) Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147. Ahima, R.S., Dushay, J., Flier, S.N., Prabakaran, D. and Flier, J.S. (1997) Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99, 391–395. Bennet, B.D., Solar, G.P., Yuan, J.O., Mathias, J., Thomas, G.R. and Matthews, W. (1996) A role for leptin and its cognate receptor in hematopoiesis. Curr. Biol. 9, 1170–1180. Umemoto, Y., Tsuji, K., Yang, F., Ebihara, Y., Kaneko, A., Furukawa, S. and Nakahata, T. (1997) Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. Blood 90, 3438–3443. Sierra-Honigmann, M.R., Nath, A.K., Murakami, C., GarciaCardena, G., Papapetropoulos, A., Sessa, W.C., Madge, L.A., Schechner, J.S., Schwabb, M.B., Polverini, P.J. and FloresRiveros, J.R. (1998) Biological action of leptin as an angiogenic factor. Science 281, 1683–1686. Bouloumie, A., Drexler, H.C., Lafontan, M. and Busse, R. (1998) Leptin, the product of Ob gene, promotes angiogenesis. Circ. Res. 83, 1059–1066. Harigaya, A., Nagashima, K., Nako, Y. and Morikawa, A. (1997) Relationship between concentration of serum leptin and fetal growth. J. Clin. Endocrinol. Metab. 82, 3281–3284. Koistinen, H.A., Koivisto, V.A., Andersson, S., Karonen, S.L., Kontula, K., Oksanen, L. and Teramo, K.A. (1997) Leptin concentration in cord blood correlates with intrauterine growth. J. Clin. Endocrinol. Metab. 82, 3328–3330.
300 [33] Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Campfield, L.A., Clark, F.T., Deeds, J., Smutko, J.S., Mays, G.G., Wolf, E.A., Monroe, C.A. and Tepper, R.I. (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271. [34] Tartaglia, L.A. (1997) The leptin receptor. J. Biol. Chem. 272, 6093–6096. [35] Lee, G.H., Proenca, R., Montez, J.M., Caroll, K.M., Darvishzadeh, J.G., Lee, J.I. and Friedman, J.M. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635. [36] Fei, H., Okano, H.J., Li, C., Lee, G.H., Zhao, C., Darnell, R. and Friedman, J.M. (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94, 7001–7005. [37] Kishimoto, T., Taga, T. and Akira, S. (1994) Cytokine signal transduction. Cell 76, 253–262. [38] Heldin, C.H. (1995) Dimerization of cell surface receptors in signal transduction. Cell 80, 213–223. [39] Elmquist, J.K., Bjorbaek, C., Ahima, R.S., Flier, J.S. and Saper, C.B. (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547. [40] Bjorbaek, C., Elmquist, J.K., Michl, P., Ahima, R.S., van Bueren, A., McCall, A.L. and Flier, J.S. (1997) Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139, 3485–3491. [41] Ghilardi, N., Ziegler, S., Wiestner, A., Stoffel, R., Heim, M.K. and Skoda, R.C. (1996) Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl. Acad. Sci. USA 93, 6231–6235. [42] Bjorbaek, C., Uotani, S., da Silva, B. and Flier, J.S. (1997) Divergent signaling capacities of the long and short isoforms of the leptin receptor. J. Biol. Chem. 273, 32686–32695. [43] Vaisse, C., Halaas, J.L., Horvath, C.M., Darnell Jr., J.E., Stoffel, M. and Friedman, J.M. (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97. [44] Hakansson, M.L. and Meister, B. (1998) Transcription factor STAT3 in leptin target neurons of the rat hypothalamus. Neuroendocrinology 68, 420–427. [45] White, D.W., Kuropatwinski, K.K., Devos, R., Baumann, H. and Tartaglia, L.A. (1997) Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J. Biol. Chem. 272, 4065–4071. [46] Bjorbaek, C., Buchholz, R.M., Davis, S.M., Bates, S.H., Pierroz, D.D., Gu, H., Neel, B.G., Myers Jr., M.G. and Flier, J.S. (2001) Divergent roles of SHP-2 in ERK activation by leptin receptors. J. Biol. Chem. 276, 4747–4755. [47] Bjorbaek, C., Lavery, H.J., Bates, S.H., Olson, R.K., Davis, S.M., Flier, J.S. and Myers Jr., M.G. (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657. [48] Banks, A.S., Davis, S.M., Bates, S.H. and Myers Jr., M.G. (2000) Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14563–14572. [49] van den Brink, G.R., OÕToole, T., Hardwick, J.C., van den Boogaardt, D.E., Versteeg, H.H., van Deventer, S.J. and Peppelenbosch, M.P. (2000) Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogenactivated protein (MAP) kinase and p70 S6 kinase. Mol. Cell. Biol. Res. Commum. 4, 144–150. [50] Gualillo, O., Eiras, S., White, D.W., Dieguez, C. and Casanueva, F.F. (2002) Leptin promotes the tyrosine phosphorylation of SHC proteins and SHC association with GRB2. Mol. Cell. Endocrinol. 190, 83–89. [51] Waelput, W., Verhee, A., Broekaert, D., Eickerman, S., Vandekerckhove, J. and Beattie, J.H. (2000) Identification and expression analysis of leptin-regulated immediate early response and late target genes. Biochem. J. 348 (1–2), 55–61. [52] Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Lavery, H.J., Haq, A.K., MaratosFlier, E., Neel, B.G., Schwartz, M.W. and Myers Jr., M.G. (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421 (6925), 856–859. [53] Faggioni, R., Feingold, K.R. and Grunfeld, C. (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J. 14, 2565–2571.
M. Otero et al. / FEBS Letters 579 (2005) 295–301 [54] Mancuso, P., Canetti, C., Gottschalk, A., Tithof, P.K. and PetersGolden, M. (2004) Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2gamma) protein expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L497–L502. [55] Zarkesh-Esfahani, H., Pockley, G., Metcalfe, R.A., Bidlingmaier, M., Wu, Z., Ajami, A., Weetman, A.P., Strasburger, C.J. and Ross, R.J. (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J. Immunol. 167, 4593–4599. [56] Raso, G.M., Pacilio, M., Esposito, E., Coppola, A., Di Carlo, R. and Meli, R. (2002) Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1. Br. J. Pharmacol. 137, 799–804. [57] Caldefie-Chezet, F., Poulin, A., Tridon, A., Sion, B. and Vasson, M.P. (2001) Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?. J. Leukoc. Biol. 69 (3), 414–418. [58] Caldefie-Chezet, F., Poulin, A. and Vasson, M.P. (2003) Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic. Res. 37 (8), 809–814. [59] Zhao, Y., Sun, R., You, L., Gao, C. and Tian, Z. (2003) Expression of leptin receptors and response to leptin stimulation of human natural killer cell lines. Biochem. Biophys. Res. Commun. 300 (2), 247–252. [60] Tian, Z., Sun, R., Wei, H. and Gao, B. (2002) Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochem. Biophys. Res. Commun. 298 (3), 297–302. [61] Dixit, V.D., Mielenz, M., Tabu´, D.D. and Parvizi, N. (2003) Leptin induces growth hormone secretion from peripheral blood mononuclear cells via a protein kinase C- and nitric oxidedependent mechanism. Endocrinology 144, 5595–5603. [62] La Cava, A. and Matarese, G. (2004) The weight of leptin in immunity. Nat. Rev. Immunol. 4 (12), 371–379. [63] Howard, J.K., Lord, G.M., Matarese, G., Vendetti, S., Ghatei, M.A., Ritter, M.A., Lechler, R.I. and Bloom, S.R. (1999) Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104 (8), 1051–1059. [64] Barbier, M., Cherbut, C., Aube, A.C., Blottiere, H.M. and Galmiche, J.P. (1998) Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 43, 783–790. [65] Tuzun, A., Uygun, A., Yesilova, Z., Ozel, A.M., Erdil, A., Yaman, H., Bagci, S., Gulsen, M., Karaeren, N. and Dagalp, K. (2004) Leptin levels in the acute stage of ulcerative colitis. J. Gastroenterol. Hepatol. 19, 429–432. [66] Sitaraman, S., Liu, X., Charrier, L., Gu, L.H., Ziegler, T.R., Gewirtz, A. and Merlin, D. (2004) Colonic leptin: source of a novel proinflammatory cytokine involved in IBD. FASEB J. 18, 696–698. [67] Siegmund, B., Sennello, J.A., Jones-Carson, J., Gamboni-Robertson, F., Lehr, H.A., Batra, A., Fedke, I., Zeitz, M. and Fantuzzi, G. (2004) Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Gut. 53, 965– 972. [68] Sanna, V., Di Giacomo, A., La Cava, A., Lechler, R.I., Fontana, S., Zappacosta, S. and Matarese, G. (2003) Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J. Clin. Invest. 111 (7), 241–250. [69] Matarese, G., Sanna, V., Di Giacomo, A., Lord, G.M., Howard, J.K., Bloom, S.R., Lechler, R.I., Fontana, S. and Zappacosta, S. (2001) Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur. J. Immunol. 31, 1324–1332. [70] Matarese, G., Sanna, V., Lechler, R.I., Sarvetnick, N., Fontana, S., Zappacosta, S. and La Cava, A. (2002) Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes 51, 1356– 1361. [71] Busso, N., So, Chobaz-Peclat, V., Morard, C., Martinez-Soria, E., Talabot-Ayer, D. and Gabay, C. (2002) Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J. Immunol. 168, 875–882. [72] Fraser, D.A., Thoen, J., Reseland, J.E., Forre, O. and KjeldsenKragh, J. (1999) Decreased CD4+ lymphocyte activation and
M. Otero et al. / FEBS Letters 579 (2005) 295–301
[73] [74] [75]
[76] [77]
increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin. Rheumatol. 18, 394–401. Bokarewa, M., Bokarew, D., Hultgren, O. and Tarkowski, A. (2003) Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 952–956. Palmer, G. and Gabay, C. (2003) A role for leptin in rheumatic diseases?. Ann. Rheum. Dis. 62 (10), 913–915. Figenschau, Y., Knutsen, G., Shahazeydi, S., Johansen, O. and Sveinbjornsson, B. (2001) Human articular chondrocytes express functional leptin receptors. Biochem. Biophys. Res. Commun. 287 (1), 190–197. Dumond, H., Presle, N., Terlain, B., Mainard, D., Loeuille, D., Netter, P. and Pottie, P. (2003) Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 48 (11), 3118–3129. Otero, M., Gomez Reino, J.J. and Gualillo, O. (2003) Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes
301
[78]
[79] [80] [81]
and ATDC5 chondrogenic cells. Arthritis Rheum. 48 (2), 404– 409. Kim, S.J., Ju, J.W., Oh, C.D., Yoon, Y.M., Song, W.K., Kim, J.H., Yoo, Y.J., Bang, O.S., Kang, S.S. and Chun, J.S. (2002) ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J. Biol. Chem. 277 (2), 1332–1339. Loeser, R.F. (2003) Systemic and local regulation of articular cartilage metabolism: where does leptin fit in the puzzle?. Arthritis Rheum. 48 (11), 3009–3012. Otero, M., Gomez-Reino, J.J. and Gualillo, O. (2003) Leptin synergizes interleukin-1 in inducing nitric oxide synthase in chondrocytes. Arthritis Rheum. 48 (9 (Suppl. S)), 654. Peelman, F., Van Beneden, K., Zabeau, L., Iserentant, H., Ulrichts, P., Defeau, D., Verhee, A., Catteeuw, D., Elewaut, D. and Tavernier, J. (2004) Mapping of the leptin binding sites and design of a leptin antagonist. J. Biol. Chem. 279 (39), 41038– 41046.
FEBS Letters 579 (2005) 295–301
Minireview
Leptin, from fat to inflammation: old questions and new insights Miguel Oteroa, Rocı´o Lagoa, Francisca Lagob, Felipe F. Casanuevac, Carlos Dieguezd, Juan Jesu´s Go´mez-Reinoe, Oreste Gualilloa,* a
Santiago University Clinical Hospital, Research Laboratory 4 (NEIRID LAB, Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago de Compostela, Spain b Santiago University Clinical Hospital, Research Laboratory 1 (Molecular and Cellular Cardiology), Santiago de Compostela, Spain c Molecular Endocrinology Section, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain d Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain e Rheumatology Division, Department of Medicine, Santiago University Clinical Hospital, University of Santiago de Compostela, Spain Received 11 August 2004; revised 9 October 2004; accepted 4 November 2004 Available online 8 December 2004 Edited by Veli-Pekka Lehto
Abstract Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses. Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: Leptin; Imflammation
1. A brief introduction Until recently, fat was considered to serve prevalently as the triglyceride reservoir of the body and was relegated to a pas* Corresponding author. Fax: +34 981 951068. E-mail address: [email protected] (O. Gualillo).
sive endocrine role. The fact that adipose tissue was identified as the major site for metabolism of sex steroid and then the discovery of the leptin, as well successively of other adipocytokines (adiponectin, resistin), changed completely this traditional view. Most of the products secreted by adipose tissue play a lead role in inflammation and immune response, namely fat cells produce interleukin-6, tumor necrosis factor a and many other cytokines and hormones including leptin. This review focuses prevalently on the complex relationships existing among leptin, inflammation processes and immune response, trying to explore the paradigms that have shaped the past decadeÕs research and what these findings forecast for the future.
2. Leptin biology overlook Leptin is a peptide hormone that is produced predominantly by white adipose cells [1,2]. The mature protein, that is encoded by the obese (ob) gene localized into human and mouse 7 and 6 chromosomes, respectively, is a 16 kDa non-glycosylated protein. Structurally, it belongs to the type I cytokine superfamily and is characterized by a long chain four-helical bundle structure, such as growth hormone, prolactin, IL-3, and others. Circulating leptin levels are proportional to adipose tissue mass. Thus, leptin levels can be considered as a signal to the body of its energy reserves. Although elevated leptin levels are present in obesity, it is likely that the physiological importance of leptin is that low levels signal starvation [3]. 2.1. Modulation of leptin expression Leptin gene expression is regulated by several factors but mainly by food intake and hormones. For example, insulin stimulates leptin secretion during feeding and a decrease of insulin levels precedes a fall in leptin concentrations during starvation in humans [4–6]. An inverse relationship between leptin and glucocorticoids has been observed, although glucocorticoids may mediate a synergic action with insulin on cultured adipocytes [7–9]. Leptin synthesis increases in response to acute infection, sepsis and secretion of inflammatory mediators as IL-1, TNF-a and LIF [10–12]. Furthermore, the expression of this hormone is inhibited by testosterone, whereas it is increased by ovarian sex steroids [13–15].
0014-5793/$22.00 Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2004.11.024
296
2.2. Leptin biological actions Central nervous system, namely hypothalamic nuclei, is the target where leptin exerts most of its effects on energy metabolism. Leptin decreases food intake, increases energy expenditure and decreases metabolic efficiency. Leptin has been shown to influence a wide spectrum of biological functions, such as lipid and glucose metabolism, synthesis of glucocorticoids, insulin, CD4+ T lymphocyte proliferation, cytokine secretion, phagocytosis and synaptic transmission [16–19]. In addition, it regulates the hypothalamic–pituitary–adrenal axis [20–22], maturation of the reproductive system [23–26], hematopoiesis [27,28], angiogenesis [29,30] and fetal development [31,32]. 2.3. Leptin receptors Leptin receptor (Ob-R) is encoded by the diabetes (db) gene that has been cloned from mouse choroid plexus [33,34]. The Ob-R mRNA is alternatively spliced giving rise to six different spliced forms of the receptor known as Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re and Ob-Rf [35,36]. Ob-R is a member of the class I cytokine receptor superfamily, which includes receptors for IL-6, LIF, CNTF, OSM, G-CSF and gp 130 with predominantly hematopoietic expression [37,38]. These receptors are membrane-spanning glycoproteins. In the extracellular region, they present fibronectin type III domains and a shared 200-amino acid module, that contains four conserved cysteine residues and the membrane proximal region WSXWS (trp-serX-trp-ser) motif. The different mRNA spliced forms encode for Ob-R with different length cytoplasmic domains: Ob-Rb, also known as the long receptor isoform, has 302 cytoplasmic residues containing the activation and signal transduction motifs; the other forms with a 34-amino acid residue cytoplasmic domain and the soluble one (Ob-Re) lacks some or all of these motifs. The short forms of leptin receptor are expressed in choroid plexus, kidney, gonads, liver, lung and vascular endothelium, where they mediate leptin transport into the brain, degradation and clearance [39,40]. Ob-Rb is primarily expressed at high levels in the hypothalamus, especially in the arcuate, dorsomedial, ventromedial and lateral hypothalamic nuclei, a crucial area that secrete neuropeptides and neurotransmitters involved in the regulation of appetite and body weight. Furthermore, the long isoform is expressed in murine and human fetal liver, jejunal epithelium, pancreatic b cells, ovarian follicular cells, vascular endothelial cells, CD34+ hematopoietic bone marrow precursors, and T lymphocytes [17,27,29,30]. 2.4. Leptin receptor signal transduction: the JAK2/STAT pathway Ligand binding to Ob-Rb activates Janus kinases (JAK2) and signal transducers and activators of transcription (STAT) proteins as occurs with the other members of the class I cytokine receptor family [41,42]. All the four membrane-bound leptin receptors contain in the cytoplasmic tail a box 1 motif, strongly conserved within most members of this receptor family, whereas box 2 and 3 motifs are found only in the long isoform. Domains 1 and 2 are involved in the interaction and activation of JAK2 tyrosine kinase that phosphorylates and activates members of the STAT family of transcription factors, such as STAT1, STAT3 and STAT5. The activation of STAT3 has been observed in vivo in the hypothalamus and requires a box 3 motif in the receptor intracellular domain [43,44]. Acti-
M. Otero et al. / FEBS Letters 579 (2005) 295–301
vated JAK2 phosphorylates tyrosine residues in the intracellular domain of Ob-Rb, providing binding motifs for SHP-2 and STAT proteins [45–47]. These transcription factors, after tyrosine-phosphorylation in response to JAK activation, translocate to the nucleus, where they activate gene transcription. In particular, leptin modulates the expression of STAT3dependent target genes in hypothalamic neurons expressing Ob-Rb, which include c-fos, c-jun, suppressor of cytokine signaling-3 and genes encoding neuropeptides such as neuropeptide Y, agouti-related peptide, cocaine- and amphetamineregulated transcript, proopiomelanocortin and thyrotropinreleasing hormone [46]. 2.5. Leptin receptor alternative signaling pathways In vitro and in vivo studies showed that Ob-Rb stimulates tyrosine phosphorylation of IRS-1, PI 3-kinase activity and SHP-2-dependent ERK1/2 activation [47,48]. On the other hand, the short form Ob-Ra, which is highly expressed in the microvessels of the blood–brain barrier, has the capacity in vitro to activate JAK2, ERK2 and to phosphorylate IRS-1 in a leptin-dose manner, but is not able to activate STAT3 and downstream target c-fos gene transcription. Furthermore, it has been shown that leptin induces a marked phosphorylation of p38 MAP kinase in human peripheral blood mononuclear cells [49]. Very recently, Gualillo et al. [50] demonstrated that leptin is able to induce intracellular signal transduction pathways alternative to JAK/STAT by inducing tyrosine phosphorylation of the SH(2) containing protein SHC. These studies, carried out on a human embryonic cell line (HEK 293) transfected with the cDNA encoding for the long form of the leptin receptor and stably expressing the receptor itself, showed that upon tyrosine phosphorylation, SHC associated with the adaptor protein, Grb-2. The formation of this complex may directly link tyrosine phosphorylation events to Ras activation and may be a critical step in proliferation and/or differentiation of cells, indicating that leptin receptor, after binding the ligand, activates several pathways for signal transduction that might lead to mitogenic effect. Very recent data have demonstrated the critical role of specific tyrosine residues conserved in the cytoplasmic domains namely those situated at positions Y985, Y1077 and Y1138 of the murine receptor. For instance, the Y1138 residue seems likely to be a typical STAT3 docking site and the sharp role of this residue was further confirmed by knock-in mice expressing a Y1138S mutated receptor. This mutation induces a deep obesity in the knocked-in mice and suggests an essential role for the Y1138, and thus also for STAT3, in leptin-regulated energy homeostasis. However, and intriguingly, infertility and other defects naturally observed in the db/db mouse were not found in the Y1138S knock-in mouse, so implying a STAT3-independent leptin receptor signaling transduction pathway [51,52].
3. Leptin: a novel immunomodulator Several studies have demonstrated that leptin circulating levels increase during infection and inflammation, suggesting that leptin is part of the immune response and host defense mechanisms. Leptin levels are acutely increased by many acute phase factors, such as TNF, IL-1 and IL-6, and during bacterial infection, or lipopolysaccharide challenge [53]. Further-
M. Otero et al. / FEBS Letters 579 (2005) 295–301
more, leptin levels are elevated during carrageenan induced rat paw edema and carrageenan-induced pleurisy [12]. Leptin, per se, acts on monocytes/macrophages by inducing eicosanoids synthesis, nitric oxide and several pro-inflammatory cytokines [54,55]. In addition, leptin potentiates IFN-c-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1 [56]. Moreover, leptin induces chemotaxis of neutrophils and the release of oxygen radicals [57,58]. Leptin also affects natural killer (NK)-cell development and activation both in vitro and in vivo [59,60]. As NK cells express OBRb and db/db mice have a deficit of NK cells resulting from abnormal NK-cell development, it is reasonable that leptin might influence the development/maintenance of a normal peripheral NK-cell pool. Indeed, an important role of OBRb in NK-cell physiology is indicated by the ability of OBRb to influence NK-cell cytotoxicity through direct activation of signal transducer and activator of transcription 3. Finally, it has recently been shown that leptin stimulates the production of growth hormone by peripheral-blood mononuclear cells through protein kinase C (PKC)- and nitric oxide-dependent pathways [61]. This effect of leptin on the production of growth hormone might be important in immune homeostasis, given the fact that this cytokine-like hormone has marked influences on immune responses by controlling the survival and proliferation of immune cells. Leptin has been demonstrated to also modulate adaptive immune response. This is divided classically into T helper 1 and 2 immune responses on the basis of the cytokine pattern produced. T helper 1 lymphocytes produce mainly pro-inflammatory cytokines that are necessary for macrophage activation and cell-mediated response, whereas T helper 2 lymphocytes secrete modulatory and anti-inflammatory peptides that are important factors for the activation of B cells and basophils. The role of leptin in adaptive immune response was recently and extensively reviewed by La Cava and Matarese [62], and here we briefly summarize some of the aspects previously exposed. Recent articles reported that leptin deficiency is responsible for the immunosuppression and thymic atrophy observed during acute starvation and reduced caloric intake [17]. The impairment of the immune response is associated with a dramatic fall in serum leptin and is reverted by exogenous leptin in rodents. Leptin in mice is necessary for an effective cell-mediated immunity and the CD4+ T lymphocytes function is suboptimal in the absence of leptin as observed in the ob/ob mice [17]. In addition, there are several evidences that leptin participates in the maintenance of thymic maturation of double positive CD4+/CD8+ cells and prevents glucocorticoids-induced apoptosis in thymocytes, since both leptin deficient mice as well as starved animals show a reduction in the thymus cortex and exogenous leptin administration is able to restore normal thymic function, increasing the number of CD4+/CD8+ T lymphocytes and reducing thymic apoptosis [63]. 3.1. Leptin and autoimmune diseases Leptin likely has an important role in autoimmune states such as those observed in inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Inflammatory bowel disease is often associated with a marked weight loss compared with non-affected individuals. In a specific intestinal inflammation model, the trinitrobenzene sulphonic acid colitis induced rats, it has been shown that plasma leptin levels were elevated, correlated with the degree of
297
inflammation, and associated with anorexia [64]. In addition, in the acute stage of ulcerative colitis, increased serum leptin levels have been found in adult male patients, suggesting that leptin levels may contribute to anorexia and weight loss [65]; furthermore, in inflamed colonic epithelial cells, leptin is expressed and released into the intestinal lumen [66]. Very recently, a key role for intestinal leptin in a immune experimental model of mice chronic intestinal inflammation has been demonstrated. Leptin actions in this model appear to be mediated by leptin receptor transduction pathway on Th-1 lymphocytes [67]. In experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis, the onset of the disease is preceded by an augment of serum leptin concentrations [68]. Noteworthy, acute starvation, which reduces serum leptin levels, delays disease onset and attenuates the symptoms. In addition, leptin-deficient ob/ob mice are resistant against encephalomyelitis. This resistance is abolished by administration of leptin, which is accompanied by a switch from a Th2 to Th1 pattern of cytokine release [69]. In type 1 diabetes, the pancreatic b-cells are destroyed by immune-inflammatory processes. The non-obese diabetic (NOD) mouse is one of the best animal model for type 1 diabetes. In NOD susceptible female mice, increased serum level of leptin precedes the onset of diabetes, whereas injection of leptin speed up the autoimmune destruction of the pancreatic b-cells and increases the IFN-c production in peripheral T-cells, arguing that leptin promotes the development of type 1 diabetes through Th1 responses [70].
3.2. Leptin and rheumatoid arthritis Leptin likely plays a major role in the pathogenesis of rheumatoid arthritis. In experimental antigen-induced arthritis, both ob/ob and db/db mice develop less severe arthritis in comparison with wild type mice and display decreased interleukin1b and tumor necrosis factor-a in the knee synovial fluid. In addition, ob/ob mice display a decreased antigen-specific T-cell proliferative response, with a lower interferon-c and a higher IL-10 secretion [71]. The increased leptin production in RA patients further argues for a role of leptin in the pathogenesis of RA. In patients with rheumatoid arthritis, it was reported that fasting leads to an improvement of different clinical and biological measures of disease activity, which was associated with a marked decrease in serum leptin and a shift towards Th2 cytokine production [72]. These features, resembling those previously depicted in ob/ob mice, suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans through the induction of Th1 responses. Bokarewa et al. [73] reported increased plasma levels of leptin in 76 patients with RA as compared with healthy controls. In this work, it has also been observed that circulating plasma concentrations of leptin were significantly higher than leptin levels in matched synovial fluid samples and that the difference between plasma and synovial fluid was particularly pronounced in non-erosive arthritis. So, these authors concluded that intra-articular leptin may exert a protective effect against the destructive course of RA. Unfortunately, these data were affected by several problems that significantly limit the interpretation of their results [74]. At joint cartilage level, it has been demonstrated that chondrocytes express leptin and its cognate long form receptor
298
M. Otero et al. / FEBS Letters 579 (2005) 295–301
Fig. 1. Schematic illustration of the pleiotropic effects of leptin at central level and in the periphery with particular attention to immune system and inflammatory response in chondrocytes.
[75,76]. Furthermore, our group has demonstrated a direct effect of leptin on chondrocytes. Actually, leptin has a synergistic effect with IFN-c on nitric oxide synthase type II induction in cultured chondrocytes [77]. Nitric oxide is a gaseous mediator, induced by a wide range of pro-inflammatory cytokines, that causes most of the inflammatory alterations on cartilage including chondrocytes phenotype loss, chondrocytes apoptosis and metalloproteases activation [78]. Therefore, leptin likely acts a typical pro-inflammatory cytokine because of its synergistic action with IFN-c on nitric oxide synthase type II (Fig. 1). Even if some data suggested a protective effect of leptin in chondrocytes [79], our results pointed on a detrimental effect on chondrocytes. To further confirm a pro-inflammatory role of leptin in cartilage, recent data obtained by our group reported a synergistic effect of leptin also with IL-1, probably the most relevant cytokine playing in inflammatory diseases such as osteoarthritis, on nitric oxide synthase type II synthesis and activity in cultured chondrocytes by a signaling pathway that involves JAK2 kinase, PI-3 kinase, MEK-1 and p38 kinase [80]. These data confirm that leptin is a pro-inflammatory cytokine, and suggests that it could be the link between obesity and inflammatory conditions, particularly those related with alterations of cartilage metabolism.
4. Concluding remarks and future perspectives Since the discovery of leptin in 1994, the volume of literature on leptin biology is impressive. Although an endless series of relevant works have been carried out in the last decade to clarify the biologic role of leptin, many cellular and molecular aspects of this adipokine in immune response and inflammatory processes remain elusive. Leptin interactions with inflamma-
tion and immune system are similar to a dynamic puzzle, but where they fit the puzzle is still unclear. Nonetheless, particularly because of the close link between nutritional status and immunity and leptin modulation by food intake, this adipokine could be considered as a new potential immunological therapeutic target in conditions where leptin is thought to promote inflammatory or autoimmune diseases. For instance, one could suggest that the stress responses of acute starvation could be beneficial in some autoimmune conditions in which leptin promotes chronic inflammation. However, the hypoleptinaemia during starvation would be a potential mechanism for increased susceptibility to infection and decreased T cell response secondary to malnutrition. One potential strategy, that at first sight appears viable to counteract undesired leptin action in inflammatory and autoimmune diseases, is the possibility to use a soluble receptor, able to assure high affinity leptin binding thereby controlling the amount of bioavailable leptin. A comparable strategy was recently introduced in the clinical practice to antagonize the detrimental effects of tumor necrosis factor in rheumatoid arthritis. Other potential therapeutic interventions to antagonize leptin can be achieved by the use of monoclonal humanized antibodies or by leptin mutants with antagonistic properties which should be able to bind the leptin receptor complex without activating it [81]. However, due to the fact that leptin investigations were initially focused on weight regulation, and considering that major leptin effect on food intake and energy expenditure occurs at the hypothalamic level and that all the above mentioned molecules do not cross the blood brain barrier, only little care has been given to the development of a protein based anti-leptin therapy. Nonetheless, based on the recent observations supporting a major role of leptin in immunity, and considering that most of the effects on the immune system and inflammatory response are mediated directly
M. Otero et al. / FEBS Letters 579 (2005) 295–301
by receptors on peripheral target cells, it should be auspicious that the development of such a molecule should be boosted as a promising therapeutic intervention for inflammatory degenerative diseases such as rheumatoid arthritis, osteoarthritis and others. In conclusion, there is an increasing evidence that leptin, besides its central effects on food intake and energy expenditure, is involved (per se or by synergistic action with other cytokines) in the pathogenesis of inflammatory and autoimmune diseases. The evidence that leptin signaling deficiency impairs humoral and cellular immune responses, and attenuates experimental inflammation models, supports the notions that a strategy focused on the block of leptin activity on peripheral cells might have intriguing therapeutic benefits.
299
[14]
[15]
[16] [17]
Acknowledgements: We thank Dr. G. Matarese for his helpful advices and for his continued support. It is reasonable that not all published data were discussed in this minireview. So, we really apologize to those whose work was not mentioned. Some of the research described in this review has been supported by Spanish Ministry of Health, Fondo de Investigacio´n Sanitaria, Instituto de Salud Carlos III (FIS 01/3137, PI 020431 and G03/152), and Xunta de Galicia. Oreste Gualillo and Francisca Lago are recipients of a research contract co-funded by SERGAS and Instituto de Salud Carlos III (Exp 00/3051, 99/3040).
References [1] Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J.M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432. [2] Ahima, R.S. and Flier, J.S. (2000) Leptin. Annu. Rev. Physiol. 62, 413–437. [3] Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E. and Flier, J.S. (1996) Role of leptin in the neuroendocrine response to fasting. Nature (London) 382, 250–252. [4] Kolaczynski, J.W., Nyce, M.R., Considine, R.V., Boden, G., Nolan, J.J., Henry, R., Mudaliar, S.R., Olefsky, J. and Caro, J.F. (1996) Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 45, 699–701. [5] Boden, G., Chen, X., Kolaczynski, J.W. and Polansky, M. (1997) Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J. Clin. Invest. 100, 1107–1113. [6] Segal, K.R., Landt, M. and Klein, S. (1996) Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45, 988–991. [7] Zakrzewska, K.E., Cusin, I., Sainsbury, A., Rohner-Jeanrenaud, F. and Jeanrenaud, B. (1997) Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. Diabetes 46, 717–719. [8] De Vos, P., Saladin, R., Auwerx, J. and Staels, B. (1995) Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J. Bio. Chem. 270, 15958–15961. [9] Elimam, A., Knutsson, U., Bronegard, M., Stierna, P., Albertsson-Wikland, K. and Marcus, C. (1998) Variations in glucocorticoid levels within the physiological range affect plasma leptin levels. Eur. J. Endocrinol. 139, 615–620. [10] Faggioni, R., Fantuzzi, G., Fuller, J., Dinarello, C.A., Feingold, K.R. and Grunfeld, C. (1998) IL-1 beta mediates leptin induction during inflammation. J. Am. J. Physiol. 274, R204–R208. [11] Sarraf, P., Frederich, R.C., Turner, E.M., Ma, G., Jaskowiak, N.T., Rivet 3rd, D.J., Flier, J.S., Lowell, B.B., Fraker, D.L. and Alexander, H.R. (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J. Exp. Med. 185, 171–175. [12] Gualillo, O., Eiras, S., Lago, F., Dieguez, C. and Casanueva, F.F. (2000) Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci. 67 (20), 2433–2441. [13] Mantzoros, C.S., Moschos, S., Avramopoulos, I., Kaklamani, V., Liolios, A., Doulgerakis, D.E., Griveas, I., Katsilambros, N. and
[18]
[19] [20] [21]
[22]
[23] [24] [25]
[26] [27] [28]
[29]
[30] [31] [32]
Flier, J.S. (1997) Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J. Clin. Endocrinol. Metab. 82, 3408–3413. Blum, W.F., Englaro, P., Hatsch, S., Juul, A., Hertel, N.T., Muller, J., Skakkebaek, N.E., Heiman, M.L., Birkett, M., Attanasio, A.M., Kiess, W. and Rascher, W. (1997) Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. Clin. Endocrinol. Metab. 82, 2904–2910. Castracane, V.D., Kraemer, R.R., Franken, M.A., Kraemer, G.R. and Gimpel, T. (1998) Serum leptin concentration in women: effect of age, obesity, and estrogen administration. Fertil. Steril. 70, 472–477. Unger, R.H., Zhou, Y.T. and Orci, L. (1999) Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc. Natl. Acad. Sci. USA 96, 2327–2332. Lord, G.M., Matarese, G., Howard, J.K., Baker, R.J., Bloom, S.R. and Lechler, R.I. (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901. Gainsford, T., Willson, T.A., Metcalf, D., Handman, E., McFarlane, C., Ng, A., Nicola, N.A., Alexander, W.S. and Hilton, D.J. (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc. Natl. Acad. Sci. USA 93, 14564–14568. Haynes, W.G., Sivitz, W.J., Morgan, D.A., Walsh, S.A. and Mark, A.L. (1997) Sympathetic and cardiorenal actions of leptin. Hypertension 30, 619–623. Yu, W.H., Kimura, M., Walczewska, A., Karanth, S. and McCann, S.M. (1997) Role of leptin in hypothalamic–pituitary function. Proc. Natl. Acad. Sci. USA 94, 1023–1028. Bornstein, S.R., Uhlmann, K., Haidan, A., Ehrhart-Bornstein, M. and Scherbaum, W.A. (1997) Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 46, 1235–1238. Heiman, M.L., Ahima, R.S., Craft, L.S., Schoner, B., Stephens, T.W. and Flier, J.S. (1997) Leptin inhibition of the hypothalamic– pituitary–adrenal axis in response to stress. Endocrinology 138, 3859–3863. Strobel, A., Issad, T., Camoin, L., Ozata, M. and Strosberg, A.D. (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet 18, 213. Chehab, F.F., Lim, M.E. and Lu, R. (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 12, 318–320. Barash, I.A., Cheung, C.C., Weigle, D.S., Ren, H., Kabigting, E.B., Kuijper, J.L., Clifton, D.K. and Steiner, R.A. (1997) Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147. Ahima, R.S., Dushay, J., Flier, S.N., Prabakaran, D. and Flier, J.S. (1997) Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99, 391–395. Bennet, B.D., Solar, G.P., Yuan, J.O., Mathias, J., Thomas, G.R. and Matthews, W. (1996) A role for leptin and its cognate receptor in hematopoiesis. Curr. Biol. 9, 1170–1180. Umemoto, Y., Tsuji, K., Yang, F., Ebihara, Y., Kaneko, A., Furukawa, S. and Nakahata, T. (1997) Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. Blood 90, 3438–3443. Sierra-Honigmann, M.R., Nath, A.K., Murakami, C., GarciaCardena, G., Papapetropoulos, A., Sessa, W.C., Madge, L.A., Schechner, J.S., Schwabb, M.B., Polverini, P.J. and FloresRiveros, J.R. (1998) Biological action of leptin as an angiogenic factor. Science 281, 1683–1686. Bouloumie, A., Drexler, H.C., Lafontan, M. and Busse, R. (1998) Leptin, the product of Ob gene, promotes angiogenesis. Circ. Res. 83, 1059–1066. Harigaya, A., Nagashima, K., Nako, Y. and Morikawa, A. (1997) Relationship between concentration of serum leptin and fetal growth. J. Clin. Endocrinol. Metab. 82, 3281–3284. Koistinen, H.A., Koivisto, V.A., Andersson, S., Karonen, S.L., Kontula, K., Oksanen, L. and Teramo, K.A. (1997) Leptin concentration in cord blood correlates with intrauterine growth. J. Clin. Endocrinol. Metab. 82, 3328–3330.
300 [33] Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Campfield, L.A., Clark, F.T., Deeds, J., Smutko, J.S., Mays, G.G., Wolf, E.A., Monroe, C.A. and Tepper, R.I. (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271. [34] Tartaglia, L.A. (1997) The leptin receptor. J. Biol. Chem. 272, 6093–6096. [35] Lee, G.H., Proenca, R., Montez, J.M., Caroll, K.M., Darvishzadeh, J.G., Lee, J.I. and Friedman, J.M. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635. [36] Fei, H., Okano, H.J., Li, C., Lee, G.H., Zhao, C., Darnell, R. and Friedman, J.M. (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94, 7001–7005. [37] Kishimoto, T., Taga, T. and Akira, S. (1994) Cytokine signal transduction. Cell 76, 253–262. [38] Heldin, C.H. (1995) Dimerization of cell surface receptors in signal transduction. Cell 80, 213–223. [39] Elmquist, J.K., Bjorbaek, C., Ahima, R.S., Flier, J.S. and Saper, C.B. (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547. [40] Bjorbaek, C., Elmquist, J.K., Michl, P., Ahima, R.S., van Bueren, A., McCall, A.L. and Flier, J.S. (1997) Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139, 3485–3491. [41] Ghilardi, N., Ziegler, S., Wiestner, A., Stoffel, R., Heim, M.K. and Skoda, R.C. (1996) Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl. Acad. Sci. USA 93, 6231–6235. [42] Bjorbaek, C., Uotani, S., da Silva, B. and Flier, J.S. (1997) Divergent signaling capacities of the long and short isoforms of the leptin receptor. J. Biol. Chem. 273, 32686–32695. [43] Vaisse, C., Halaas, J.L., Horvath, C.M., Darnell Jr., J.E., Stoffel, M. and Friedman, J.M. (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97. [44] Hakansson, M.L. and Meister, B. (1998) Transcription factor STAT3 in leptin target neurons of the rat hypothalamus. Neuroendocrinology 68, 420–427. [45] White, D.W., Kuropatwinski, K.K., Devos, R., Baumann, H. and Tartaglia, L.A. (1997) Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J. Biol. Chem. 272, 4065–4071. [46] Bjorbaek, C., Buchholz, R.M., Davis, S.M., Bates, S.H., Pierroz, D.D., Gu, H., Neel, B.G., Myers Jr., M.G. and Flier, J.S. (2001) Divergent roles of SHP-2 in ERK activation by leptin receptors. J. Biol. Chem. 276, 4747–4755. [47] Bjorbaek, C., Lavery, H.J., Bates, S.H., Olson, R.K., Davis, S.M., Flier, J.S. and Myers Jr., M.G. (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657. [48] Banks, A.S., Davis, S.M., Bates, S.H. and Myers Jr., M.G. (2000) Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14563–14572. [49] van den Brink, G.R., OÕToole, T., Hardwick, J.C., van den Boogaardt, D.E., Versteeg, H.H., van Deventer, S.J. and Peppelenbosch, M.P. (2000) Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogenactivated protein (MAP) kinase and p70 S6 kinase. Mol. Cell. Biol. Res. Commum. 4, 144–150. [50] Gualillo, O., Eiras, S., White, D.W., Dieguez, C. and Casanueva, F.F. (2002) Leptin promotes the tyrosine phosphorylation of SHC proteins and SHC association with GRB2. Mol. Cell. Endocrinol. 190, 83–89. [51] Waelput, W., Verhee, A., Broekaert, D., Eickerman, S., Vandekerckhove, J. and Beattie, J.H. (2000) Identification and expression analysis of leptin-regulated immediate early response and late target genes. Biochem. J. 348 (1–2), 55–61. [52] Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Lavery, H.J., Haq, A.K., MaratosFlier, E., Neel, B.G., Schwartz, M.W. and Myers Jr., M.G. (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421 (6925), 856–859. [53] Faggioni, R., Feingold, K.R. and Grunfeld, C. (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J. 14, 2565–2571.
M. Otero et al. / FEBS Letters 579 (2005) 295–301 [54] Mancuso, P., Canetti, C., Gottschalk, A., Tithof, P.K. and PetersGolden, M. (2004) Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2gamma) protein expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L497–L502. [55] Zarkesh-Esfahani, H., Pockley, G., Metcalfe, R.A., Bidlingmaier, M., Wu, Z., Ajami, A., Weetman, A.P., Strasburger, C.J. and Ross, R.J. (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J. Immunol. 167, 4593–4599. [56] Raso, G.M., Pacilio, M., Esposito, E., Coppola, A., Di Carlo, R. and Meli, R. (2002) Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1. Br. J. Pharmacol. 137, 799–804. [57] Caldefie-Chezet, F., Poulin, A., Tridon, A., Sion, B. and Vasson, M.P. (2001) Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?. J. Leukoc. Biol. 69 (3), 414–418. [58] Caldefie-Chezet, F., Poulin, A. and Vasson, M.P. (2003) Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic. Res. 37 (8), 809–814. [59] Zhao, Y., Sun, R., You, L., Gao, C. and Tian, Z. (2003) Expression of leptin receptors and response to leptin stimulation of human natural killer cell lines. Biochem. Biophys. Res. Commun. 300 (2), 247–252. [60] Tian, Z., Sun, R., Wei, H. and Gao, B. (2002) Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochem. Biophys. Res. Commun. 298 (3), 297–302. [61] Dixit, V.D., Mielenz, M., Tabu´, D.D. and Parvizi, N. (2003) Leptin induces growth hormone secretion from peripheral blood mononuclear cells via a protein kinase C- and nitric oxidedependent mechanism. Endocrinology 144, 5595–5603. [62] La Cava, A. and Matarese, G. (2004) The weight of leptin in immunity. Nat. Rev. Immunol. 4 (12), 371–379. [63] Howard, J.K., Lord, G.M., Matarese, G., Vendetti, S., Ghatei, M.A., Ritter, M.A., Lechler, R.I. and Bloom, S.R. (1999) Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104 (8), 1051–1059. [64] Barbier, M., Cherbut, C., Aube, A.C., Blottiere, H.M. and Galmiche, J.P. (1998) Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 43, 783–790. [65] Tuzun, A., Uygun, A., Yesilova, Z., Ozel, A.M., Erdil, A., Yaman, H., Bagci, S., Gulsen, M., Karaeren, N. and Dagalp, K. (2004) Leptin levels in the acute stage of ulcerative colitis. J. Gastroenterol. Hepatol. 19, 429–432. [66] Sitaraman, S., Liu, X., Charrier, L., Gu, L.H., Ziegler, T.R., Gewirtz, A. and Merlin, D. (2004) Colonic leptin: source of a novel proinflammatory cytokine involved in IBD. FASEB J. 18, 696–698. [67] Siegmund, B., Sennello, J.A., Jones-Carson, J., Gamboni-Robertson, F., Lehr, H.A., Batra, A., Fedke, I., Zeitz, M. and Fantuzzi, G. (2004) Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Gut. 53, 965– 972. [68] Sanna, V., Di Giacomo, A., La Cava, A., Lechler, R.I., Fontana, S., Zappacosta, S. and Matarese, G. (2003) Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J. Clin. Invest. 111 (7), 241–250. [69] Matarese, G., Sanna, V., Di Giacomo, A., Lord, G.M., Howard, J.K., Bloom, S.R., Lechler, R.I., Fontana, S. and Zappacosta, S. (2001) Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur. J. Immunol. 31, 1324–1332. [70] Matarese, G., Sanna, V., Lechler, R.I., Sarvetnick, N., Fontana, S., Zappacosta, S. and La Cava, A. (2002) Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes 51, 1356– 1361. [71] Busso, N., So, Chobaz-Peclat, V., Morard, C., Martinez-Soria, E., Talabot-Ayer, D. and Gabay, C. (2002) Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J. Immunol. 168, 875–882. [72] Fraser, D.A., Thoen, J., Reseland, J.E., Forre, O. and KjeldsenKragh, J. (1999) Decreased CD4+ lymphocyte activation and
M. Otero et al. / FEBS Letters 579 (2005) 295–301
[73] [74] [75]
[76] [77]
increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin. Rheumatol. 18, 394–401. Bokarewa, M., Bokarew, D., Hultgren, O. and Tarkowski, A. (2003) Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 952–956. Palmer, G. and Gabay, C. (2003) A role for leptin in rheumatic diseases?. Ann. Rheum. Dis. 62 (10), 913–915. Figenschau, Y., Knutsen, G., Shahazeydi, S., Johansen, O. and Sveinbjornsson, B. (2001) Human articular chondrocytes express functional leptin receptors. Biochem. Biophys. Res. Commun. 287 (1), 190–197. Dumond, H., Presle, N., Terlain, B., Mainard, D., Loeuille, D., Netter, P. and Pottie, P. (2003) Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 48 (11), 3118–3129. Otero, M., Gomez Reino, J.J. and Gualillo, O. (2003) Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes
301
[78]
[79] [80] [81]
and ATDC5 chondrogenic cells. Arthritis Rheum. 48 (2), 404– 409. Kim, S.J., Ju, J.W., Oh, C.D., Yoon, Y.M., Song, W.K., Kim, J.H., Yoo, Y.J., Bang, O.S., Kang, S.S. and Chun, J.S. (2002) ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J. Biol. Chem. 277 (2), 1332–1339. Loeser, R.F. (2003) Systemic and local regulation of articular cartilage metabolism: where does leptin fit in the puzzle?. Arthritis Rheum. 48 (11), 3009–3012. Otero, M., Gomez-Reino, J.J. and Gualillo, O. (2003) Leptin synergizes interleukin-1 in inducing nitric oxide synthase in chondrocytes. Arthritis Rheum. 48 (9 (Suppl. S)), 654. Peelman, F., Van Beneden, K., Zabeau, L., Iserentant, H., Ulrichts, P., Defeau, D., Verhee, A., Catteeuw, D., Elewaut, D. and Tavernier, J. (2004) Mapping of the leptin binding sites and design of a leptin antagonist. J. Biol. Chem. 279 (39), 41038– 41046.