Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice

Siegmund, Britta; Sennello, Joseph A.; Jones-Carson, Jessica; Gamboni‐Robertson, Fabia; Lehr, Hans‐Anton; Batra, Arvind; Fedke, Inka; Zeitz, Martin; Fantuzzi, Giamila

doi:10.1136/gut.2003.027136

Cited by 125 publications

(90 citation statements)

References 28 publications

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“…The leptin receptor (Ob-R), a member of class I cytokine receptors, is encoded by the diabetes (db) gene and is expressed in peripheral B cells, T cells, NK cells, and monocyte macrophages (2)(3)(4)(5)(6). Leptin has been increasingly recognized as a cytokine-like hormone with pleiotropic actions in modulating immune responses (7).…”

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confidence: 99%

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Lam

Zheng

Jin

et al. 2007

Journal of Biological Chemistry

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Increasing evidence suggests a regulatory role for leptin, an adipocyte-derived hormone, in immunity. Although recent studies indicated an essential role of leptin signaling in dendritic cell (DC) maturation, the molecular mechanisms by which leptin modulates DC functional maturation remained unclear. In this study, we showed that leptin induced CD40 expression in murine DC and significantly up-regulated their immunostimulatory function in driving T cell proliferation. Moreover, leptin markedly enhanced lipopolysaccharide-mediated DC activation. Using pharmacological inhibitors for Akt, STAT-1␣, or NF-B and the dominant negative forms of Akt and IB kinase ␣/␤/␥, as well as small interfering RNA for STAT-1␣, we showed that Akt, STAT-1␣, and NF-B were important for the leptin-or lipopolysaccharide-induced CD40 expression. Coimmunoprecipitation analysis revealed that leptin promoted immune complex formation between Akt and the IB kinase subunits as well as STAT-1␣. Blocking the activity of Akt demonstrated a crucial role for Akt in translocation of STAT-1␣ and NF-B to the nucleus and activation of the CD40 promoter. Further analysis with chromatin immunoprecipitation assay confirmed that leptin recruited STAT-1␣, NF-Bp65, and RNA polymerase II to the CD40 promoter and enhanced histone 4 acetylation in a time-dependent manner. Thus, our results have elucidated the molecular mechanisms underlying leptin-induced CD40 expression and DC maturation.Leptin, encoded by the obese (ob) gene, is an adipocyte-derived hormone that has long been recognized as a satiety factor in regulating nutrient intake and energy homeostasis (1). Leptin is structurally related to members of the long chain helical cytokines such as IL-6, 2 IL-11, IL-12, and granulocyte colony-stimulating factor. The leptin receptor (Ob-R), a member of class I cytokine receptors, is encoded by the diabetes (db) gene and is expressed in peripheral B cells, T cells, NK cells, and monocyte macrophages (2-6). Leptin has been increasingly recognized as a cytokine-like hormone with pleiotropic actions in modulating immune responses (7). It has been shown that leptin can modulate the adaptive immunity via enhancing T cell survival and stimulating their production of pro-inflammatory cytokines such as interferon ␥ and IL-2 (8). Moreover, leptin activates NK cells and monocyte macrophages and enhances their immune functions and cytokine production (3, 9). Recent studies indicate that leptin promotes differentiation and survival of human DC (10). We also demonstrated the expression of functional leptin receptor on murine DC and revealed significantly impaired maturation and survival of bone marrow (BM)-derived DC in leptin-receptor deficient db/db mice (11), but the underlying molecular mechanisms by which leptin regulates DC maturation and function remained largely unclear. DC are the most potent antigen-presenting cells and undergo maturation process by up-regulating the expression of MHC and costimulatory molecules and become phenotypically and functionally differenti...

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confidence: 99%

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Lam

Zheng

Jin

et al. 2007

Journal of Biological Chemistry

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“…A histological observation of the colon revealed marked inflammation in mice injected with wild-type cells, whereas no inflammation was observed in mice receiving db/db cells. 44,89 Serum leptin levels are not altered in human inflammatory bowel diseases, although they might increase during the acute stages of ulcerative colitis. Furthermore, leptin mRNA is upregulated in mesenteric adipose tissue of these patients.…”

Section: Leptin Connective Tissue Diseases and Organ-specific Autoimmentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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“…Despite the name 'eosinophilic', EGCs may have different staining affinities, basophilic or eosinophilic, depending on the species considered and the conditions of fixation (Rocha & Chiarini-Garcia 2007). The involvement of leptin in inflammation is well-established in birds and mammals (Lõhmus et al 2004;Matarese et al 2005); in particular, it has been demonstrated that, in the mammalian intestine, lymphocytes release leptin at the inflammation site (Siegmund et al 2004;Fantuzzi et al 2005). Our data therefore suggest that leptin can be involved in immune and inflammatory responses in teleosts, in addition to its better-known role as a regulator of energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Immunolocalisation of leptin in the digestive system of juvenile European sea bass (Dicentrarchus labrax)

Gambardella

Ferrando

et al. 2010

Italian Journal of Zoology

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Leptin is a hormone that is mainly produced by adipocytes; it is connected with metabolism regulation, but knowledge about its effect on teleosts, particularly in juvenile specimens, is still scarce. This study is the first to investigate the presence of leptin immunoreactivity in juvenile European sea bass (Dicentrarchus labrax) and its distribution in the digestive system. Leptin immunoreactivity was detected by Western blot analysis, while its distribution was obtained using immunohistochemical methods with a human leptin-specific antibody. The homogenate of the body of a whole European sea bass contains a leptin-like protein with an estimated molecular weight of approximately 16 kDa. Leptin immunoreactivity was distributed along the digestive system, especially in the oesophageal mucous cells, neuroendocrine gastrointestinal cells and eosinophilic granular cells of the gastrointestinal lamina propria. This is the first report on leptin immunoreactivity in juvenile sea bass and our data can provide a good morphological basis for further investigation into food, metabolism and immunoresponse regulation in aquacultured fish.

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Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice

Cited by 125 publications

References 28 publications

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Leptin in immuno-rheumatological diseases

Immunolocalisation of leptin in the digestive system of juvenile European sea bass (Dicentrarchus labrax)

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