SummaryLeptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research. In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. However, the manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. The purpose of this review is to provide background information on the leptin and ghrelin hormones, their role in food intake and body weight in humans, and their mechanism of action. Possible abnormalities in the leptin and ghrelin systems that may contribute to the development of obesity will be mentioned. In addition, the potentials of leptin and ghrelin as drug targets will be discussed. Finally, the influence of the diet on leptin and ghrelin secretion and functioning will be described.

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and ␤-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress ␤-catenin, including its N-terminally unphosphorylated form, suggesting active ␤-catenin͞T cell factor-mediated transcription. Further accumulation and nuclear localization of ␤-catenin, and͞or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of ␤-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer.␤-catenin ͉ T cell factor ͉ lymphoma ͉ plasma cell

Integrin-mediated adhesion and B cell antigen receptor (BCR) signaling play a critical role in B cell development and function, including antigen-specific B cell differentiation. Here we show that the BCR controls integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 and fibronectin. Molecular dissection of the underlying signaling mechanism by a combined biochemical, pharmacological, and genetic approach demonstrates that this BCR-controlled integrin-mediated adhesion requires the (consecutive) activation of Lyn, Syk, phosphatidylinositol 3-kinase, Bruton's tyrosine kinase (Btk), phospholipase C (PLC)γ2, IP3R-mediated Ca2+ release, and PKC. In contrast, activation of mitogen-activated protein kinase kinase (MEK) or extracellular signal–regulated kinase (ERK) is not required, and simultaneous activation of MEK, ERK, and PKB is not sufficient either. Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells. The control of integrin α4β1-mediated B cell adhesion by the BCR involves cytoskeletal reorganization and integrin clustering. These results reveal a novel function for the BCR and Btk, i.e., regulation of integrin α4β1 activity, thereby providing new insights into the control of B cell development and differentiation, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulineamia (XLA).

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Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

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Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lympho- IntroductionB-cell lymphomas represent the malignant counterparts of normal B cells, arrested at specific maturational stages. They are classified into distinct disease categories based on their stage-specific morphologic features, molecular profile, and B-cell receptor (BCR) configuration. 1 The initial step in lymphomagenesis is the acquisition of a genetic aberration, most often a chromosomal translocation involving a proto-oncogene, causing an increased life span and/or enhanced proliferation. 2 In general, this event per se is not tumorigenic, but further (multiple) genetic alterations are required for the development of a fully malignant phenotype. In addition to these oncogenic events, B-cell malignancies require signals from the microenvironment for their growth, survival, and progression. These signals, which include B-cell receptor (BCR) stimulation by antigen, 3 physical contact of (malignant) B cells with stromal cells via integrin adhesion receptors, 4-7 as well as a number of cytokines/ growth factors, 8 activate intracellular signaling cascades and present potential targets for therapeutic intervention. One of the candidate growth factors in B-cell malignancies is hepatocyte growth factor (HGF). [9][10][11] HGF induces complex biologic responses in target cells, including adhesion, motility, growth, survival, and morphogenesis, by activating the tyrosine kinase receptor MET. HGF/MET signaling is indispensable for mammalian development, while uncontrolled activation of MET is oncogenic and has been implicated in the growth, invasion, and metastasis of a variety of tumors. 12,13 Several distinct mechanisms may underlie uncontrolled MET activation. These include translocation, amplification, or mutation of the MET gene, 12,[14][15][16][17][18][19] and autocrine or paracrine HGF production. 14,20,21 In B cells, the HGF/MET pathway has been implicated in differentiation, specifically in the regulation of adhesion and migration. 13,22 We have previously demonstrated that the MET protein is expressed on GC B cells, 22 whereas follicular dendritic cells (FDCs) and stromal cells express HGF. 22,23 Furthermore, we and others have identified the HGF/MET pathway as a potentially important signaling route in lymphomagenesis. 9,13,24,25 In several B-cell malignancies, including multiple myeloma (MM), 24,26,27 primary effusion lymphoma (PEL), 28 and Hodgkin lymphoma (HL), 9 coexpression of HGF and MET has been observed, suggesting autocrine activation of HGF/MET signaling. Furthermore, in MM, HL, and d...