Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 11, Issue 4, 2011

Beta cell apoptosis and suboptimal islet function are implicated in the development of Type I (T1D) and Type II (T2D) diabetes, as well as the failure of the only current clinical beta cell replacement therapy for T1D, islet transplantation. Sphingosine kinase (SK) is a ubiquitous lipid kinase that controls the balance between prosurvival and proapoptotic precursors (e.g. sphingosine-1-phosphate (S1P) and ceramide, respectively), the so-called 'sphingolipid rheostat', in many cell types. S1P, a potent lipid mediator, acts intracellularly through second messengers and extracellularly through five G-protein coupled receptors (S1P1-5), to promote calcium mobilization, intracellular signaling events, cytoskeleton rearrangements and mitogenesis. SK is important for revascularization responses, regulating the maturation of vascular endothelial progenitors and controlling cellular recruitment. The aim of this review is to highlight the sphingolipid rheostat in pancreatic biology as a therapeutic target for pharmacological and therapeutic intervention for diabetes and islet transplantation. SK and the sphingolipid rheostat are likely to be important for both islet function and beta cell survival and represent a common therapeutic target to protect the beta cell from diabetogenic insults and ultimately improve pancreatic islet function. A number of SK inhibitors and S1P receptor agonists/antagonists (including FTY720 (fingolimod) and its newer derivatives) have been recently described, with some now being used in the clinic. Recent developments in SK biochemistry and islet biology indicate the potential importance of the sphingolipid rheostat in determining islet survival and function. Pharmacological manipulation of this pathway represents a novel therapeutic strategy to prevent diabetes and improve islet transplantation outcomes.

The association between metabolic syndrome and cardiovascular diseases raises important questions about the underlying pathological processes, especially for designing targeted therapeutic interventions. The Peroxisome Proliferators Activated Receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. Accumulating data suggest that PPARs may serve as potential targets for treating metabolic diseases and their cardiovascular complications. PPARs regulate gene expression by binding with RXR as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/δ and γ, have been identified. PPARα and PPARγ are the most extensively examined and characterized, mainly because they are activated by compounds, such as fibrates and thiazolidinediones, that are in clinical use for the treatment of hypertriglyceridemia and insulin resistance, respectively. In contrast the role of PPARβ/δ in metabolism has been less investigated. The recent availability of specific PPARβ/δ agonists revealed that PPARβ/δ plays a crucial role in fatty acid metabolism in several tissues. Besides, PPARβ/δ activation exerts beneficial effects against organ-related ischemic events, such as myocardial and cerebral infarction, which are among the most critical cardiovascular complications evoked by metabolic dysregulation. This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPARβ/δ agonists in the treatment of metabolic syndrome and its associated cardiovascular risk factors.

Obesity due to endocrine and metabolic disorders causing dysfunctions of appetite-regulating pathways and energy balance is an increasingly concerning issue. Such form of obesity is mainly caused by the failure of elevated levels of the hormone leptin (LEP) to suppress feeding and mediate weight loss; the syndrome, caused by disruptions of signal transduction processes at the level of leptin receptors (LEPR), has been named as leptin resistance. Alterations in genes coding for LEPR and other hypothalamic factors in obese individuals have been related to low rates of pregnancies and deliveries. Fertility depends mainly on the success of processes involving ovulation, fertilization, implantation, placentation and embryo development; processes that seem to be affected in obese females. However, mechanistical research in human beings is very difficult to undertake, especially in reproductive issues, for both technical and ethical reasons. Thus, investigation is usually taken on animal models. Most of the studies have been carried out in mice, in which mutations in LEP and LEPR genes cause severe obese phenotypes (Leprob/ob and Leprdb/db mouse); in addition, such genotypes are infertile. However, total loss of LEPR function by monogenic disorders in humans, unlike mice, are really scarce. Functional alterations by LEPR gene polymorphisms are more common; the same has been found in the swine, an animal model very close to human. This review outlines, from results of translational animal research and clinical studies, the factors, mechanisms and pathways involved in the reproductive failures of individuals with metabolic disorders during the critical period from ovulation to completion of placentation and early-embryo development.

The FGF family comprises twenty-two evolutionarily related members with diverse functions in development, metabolism, and neuronal activities. FGF10 and FGF21 play unique roles in adipocyte development and metabolism, respectively. FGF10 mediates biological responses by activating FGF receptor 2b (FGFR2b) with heparin/heparan sulfate in a paracrine manner. In contrast, FGF21 mediates biological responses by activating FGFRs with βKlotho in cultured cells. However, FGF21 acts in an autocrine manner via a β Klotho-independent signaling pathway in mice. Fgf10 knockout mice die shortly after birth. Preadipocyte proliferation and adipogenesis are greatly impaired in Fgf10 knockout mouse embryos. FGF10 stimulates preadipocyte proliferation through the Ras/MAPK pathway followed by the cyclin D2-dependent phosphorylation of p130. FGF10 also stimulates adipogenesis by inducing the expression of pRb through the Ras/MAPK pathway. pRb binds C/EBPα. The pRb-C/EBPα complex induces adipogenesis. Fgf21 is abundantly expressed in the liver. Hepatic Fgf21 expression is markedly induced in mice by fasting. FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes. However, the phenotypes of Fgf21 knockout mice, which are apparently normal and fertile, indicate FGF21 not to be a physiological regulator for hepatic functions. Hepatic FGF21 inhibits lipolysis in adipoctyes, and so is a negative regulator of lipolysis during fasting. FGF21 may be a “thrifty factor”. Serum FGF21 levels are increased in patients with metabolic diseases related with obesity, indicating potential roles of FGF21 in adipocyte metabolism.

Endothelial cells (ECs) express on their membrane Toll like receptor (TLR)-4 and, therefore, are able to interact with lipopolysaccharides (LPS) or endotoxins, major constituents of the Gram-negative bacteria outer membrane. The impact of LPS on ECs can be either direct or mediated via release of cytokines and/or chemokines originated from monocytes/macrophages. In this review, the effect of the interaction between LPS and ECs on the outcome of various human diseases such as preeclampsia, hereditary haemorrhagic teleangiectasia, atherosclerosis and sepsis will be illustrated. Finally, the major therapeutic attempts aimed at neutralizing LPS and, therefore, their influence on ECs will be discussed.

Poly(ADP-ribose) polymerases (PARPs) represent a family of enzymes which synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate. PARP-1, the prototypical representative of the family, accounts for the majority of the poly(ADP-ribose) polymer synthesis. PARP-1 functions as a DNA nick sensor and signaling molecule binding to ssDNA and dsDNA protecting cells from genomic instability. PARP-1 activity plays a relevant role in the development of inflammatory responses largely contributing to tissue damage in ischemia/reperfusion conditions, such as stroke and myocardial infarction, and in septic shock. Recently, several findings revealed a wider immunological role for PARP-1. It regulates gene transcription in several types of immune cells, including dendritic cells, macrophages and lymphocytes. PARP-1 affects the stimulatory ability of dendritic cells, T cell activation and antibody production. Inhibition of PARP-1 enzymatic activity reduces the secretion of pro-inflammatory cytokines and ameliorates autoimmune diseases in several experimental models. Our recent findings showed that PARP-1 deficiency affects T cell differentiation rendering naïve CD4 T cells prone to differentiate in regulatory T cells. All together these findings show that PARP-1 plays a pivotal role in the balance between pro-inflammatory/effector and anti-inflammatory/regulatory responses, opening new possible therapeutic perspectives.

Regulatory T (Treg) cells play an important role in the maintenance of self-tolerance and are involved in the prevention of autoimmune diseases and reduce/inhibit the progression of chronic inflammatory diseases. Forkhead box P3 (FoxP3) expression in Treg cells is believed to be a critical factor in the maintenance of Treg cells suppressive function. Multiple mechanisms of action of Treg cells have been proposed, including cell contact-dependent and cytokinedependent mechanisms. However, no clear picture is available to fully elucidate the regulation of FoxP3 gene expression in Treg cells and how FoxP3-expressing Treg cells mediate the immune response in vivo. This review will discuss the research advancements in Treg cell biology including the transcription factors and signaling pathways involved in the expression of FoxP3 gene as well as the advancements in the understanding of the factors involved in the Treg cell-mediated suppressive mechanisms.