Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 7, Issue 2, 2007

A paradigm-shifting discovery of leptin in 1994 attracted researchers' attention on the endocrine and paracrine functions of adipose tissue, although the birth hour of adipoendocrinology could be traced back to the mid 1980s when lipoprotein lipase and adipsin were identified as adipose-derived endocrine products. In expressing their secretory phenotype, adipocytes, tissue matrix cells, stromovascular cells and immune cells associated with adipose tissue produce and release a wealth of moonlighting proteins designated adipokines or adipocytokines. Extensive research in the past decade has identified about hundred adipokines as constituting the adipokinome (secretory proteome). These studies clearly shown that adipokines play a crucial role in the pathogenesis of variety of diseases besides obesity and related disorders. This intellectual growth was conseptualized as a novel field of study dubbed adipobiology of disease (Curr. Pharm. Des., 2003, 9, 1023). Accordingly, lingua adipobiologica has been progressively enriched with terms such as adipokines, adipocytokines, adipokinome, adiponectin, adipoendocrinology, adipopharmacology, adipomics alike. This topic issue is a product of collaborative work of the contributors and Guest Editor, and presents eight reviews on various aspects of adipobiology of disease. Its state-of-the-science format aims at serving as a useful reference and educational tool, as well as to assist the medical community in its efforts on research, prevention and therapy of diseases associated with dysregulated adipose tissue. The present challenge is to cultivate an adipocentric thinking of how we can make adipokines and other adipose-derived molecules work for the benefit of human's health. Perhaps, the field of adipobiology is grown enough for a systems biology approach that may integrate data of immunology, endocrinology and metabolism at the “-omics” level. This may contribute to the development of adipopharmacology because the adipokines' pleiotropic activities put them forward as a multifaceted target of pharmaceutical and nutraceutical agents. The Editor hopes that the data and hypotheses presented here will foster the interaction between scientists and clinicians. And will convey to the reader some of the excitement that enlivens the current progress of adipobiology. We may thus share together the importance of Albert Einstein's statement about the exchange of apples and ideas. Also its in vivo phenotypic expression: the First International Symposium on Adipobiology and Adipopharmacology (ISAA) to be held 19-21 October 2007 in Varna, Bulgaria (www.bgscb.org/Browse_Archives.htm and www.nutrigenomics-bg.com).

The adipose tissue-derived protein adiponectin is involved in the regulation of insulin sensitivity, inflammation and immunity. Circulating levels of this adipocytokine are decreased in obesity and diseases associated with insulin resistance. Besides its major role in regulation of hepatic insulin sensitivity, recent evidence suggests a strong antiinflammatory function for this pleiotropic mediator. Whereas initial studies demonstrated that adiponectin suppresses primarily the pro-inflammatory cytokine tumor necrosis factor-alpha, current studies show that it induces anti-inflammatory cytokines such as interleukin-10 or IL-1 receptor antagonist. These effects are paralleled by other immune-regulatory properties such as downregulation of endothelial cell adhesion molecules. This adipocytokine suppresses inflammation in various models of liver and myocardial injury. Adiponectin exerts its biological functions by interacting with adiponectin receptor type 1 and 2 as well as T-cadherin. Adiponectin is a key mediator regulating and affecting processes between adipose tissue, inflammation and immunity. Therefore, adiponectin, adiponectin secretion-stimulating agents or adiponectin receptor agonists might be of clinical relevance in many diseases beyond those associated with insulin resistance. Better knowledge of the complex biology of adiponectin and its receptors may indeed provide novel therapeutic approaches.

At an adipobiological level, obesity and insulin resistance have been better elucidated in recent years. However, the molecular factors which upregulate insulin resistance phenotype in obesity are still unclear. Adipocytes and nonadipocytes of adipose tissue are increasingly recognized as endocrine and paracrine cells producing numerous signaling proteins, collectively termed adipokines. Along with their implications for various biological functions, adipokines profoundly influence insulin sensitivity and glucose metabolism. Furthermore, the insulin-sensitizing drugs thiazolidinediones as well as insulin resistance-inducing hormones, including β-adrenergic agonists, insulin, glucocorticoids, and growth hormone, mediate, at least in part, their effects via differential regulation of adipokines. Here we present a state-of-the-art focusing on adiponectin, IL-6, leptin, TNF-α , resistin, MCP-1 (CCL2), PAI-1, SPARC (osteonectin), visfatin, vaspin, RBP-4, and NGF. Further studies in adipokine-targeted pharmacology may reveal many potential targets for anti-obesity and anti-diabetic drug development.

Accumulating basic and clinical studies indicate that adipose tissue cells (adipocytes, matrix cells, stromovascular cells and associated macrophages) synthesize and release multiple signaling proteins collectively termed adipokines. Adipokines regulate a broad spectrum of biological processes, with glucose and lipid metabolism being a key example. This defines a new field of study: adipobiology of type 2 diabetes mellitus. The importance of diabetes-related (diabetogenic) adipokines, with an emphasis on adiponectin, resistin, leptin, angiotensin II, tumor necrosis factor-α , interleukin-6, and visfatin, is reviewed. Competing of pro- and anti-diabetogenic adipokine-mediated signals may pivotally be involved in the adipobiology of diabetes. This paradigm may reveal further new tools for drug development against diabetes and related disorders.

Considered for a long time merely as an inert tissue exclusively devoted to energy storage, white adipose tissue is currently viewed as a very active secretory organ, participating in the regulation of several physiological and pathological processes, including immunity and inflammation. Adipocytes and other cells associated with adipose tissue produce and release a dazzling variety of immunomodulatory and pro- and anti-inflammatory factors, including the adipokines leptin, adiponectin, visfatin, and resistin as well as cytokines, chemokines and other mediators. Similarities between adipocytes and macrophages, as well as cross-talk between adipocytes and immune cells, make adipose tissue a direct contributor in coordinating the immune and inflammatory response. In contrast, reduced adiposity predisposes to increased susceptibility to infection in malnourished individuals. Finally, altered systemic or local levels of adipose-derived factors are observed in a variety of inflammatory and autoimmune conditions such as obesity, type 2 diabetes mellitus, atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Thus, adipose tissue acts as an active coordinator of body homeostasis, in part by modulating activation of the immune-inflammatory system.

Clinical and experimental studies provide increasing evidence that obesity is a major cardiovascular risk factor and that the adipose tissue is not just for regulation of lipid and energy homeostasis. Accordingly, the endocrine secretion of adipose tissue is implicated in the pathogenesis of vascular diseases. Whilst the functions of visceral and subcutaneous adipose tissue are relatively well studied, the role of perivascular adipose tissue in regulation of vascular functions is usually ignored. Emerging evidence indicates that perivascular adipose tissue is involved in the regulation of various physiological and pathological processes such as vascular smooth muscle contraction, vascular wall remodeling and inflammation, and, consequently, atherosclerosis and hypertension. Here we present an updated overview of vascular adipobiology, focusing on perivascular adipose tissue.

Both obesity and lipodystrophy are associated with an accumulation of lipid in tissues other than the classical adipose tissue depots. The consequences of this ectopic fat are not limited to the now well established insulin resistance but also a range of other organ specific sequelae. We discuss, with specific reference to the heart, the potential role of ectopic adipocyte proliferation as well as intracellular lipid accumulation. This is a relatively recently described phenomenon, but has attracted the attention of scientists because of the association with visceral obesity. A range of therapeutic agents have been shown to be effective in targeting ectopic fat with much evidence supporting the role of peroxisome proliferator- activated receptor-gamma agonists. Other novel approaches are emerging from the raft of studies into both human and rodent adipobiology, but it is too early to say if intervention brings any clinical benefits.

An extensive research in the last few years has identified about hundred adipose tissue-secreted proteins, named adipokines or adipocytokines. However, our knowledge of the structures and molecules involved in the intracellular secretory pathway (synthesis, translocation, folding, targeting, sorting, storage, and exocytosis) of adipokines is at present limited. Relatively more is known about insulin-responsive trafficking of glucose transporters (GLUTs). Adipokines have multiple biological functions beyond lipid and carbohydrate metabolism, whereas GLUT4 is the major glucose transporter of adipocytes and skeletal muscles. Adipokines play an important role in the pathogenesis of a wide variety of diseases, and dysregulation of GLUT4 transport is implicated in insulin resistance and related disorders. Conceptually, adipobiology of disease has emerged as a novel field of studies in basic and clinical medicine. Here we present a state-ofthe- science on some aspects of these studies with a special reference to the intracellular secretory pathway, focusing on adiponectin, GLUT4, and nerve growth factor (NGF), and suggesting that each step of this pathway may be a potential drug target. Given the beneficial effects of adiponectin, NGF and GLUT4 on various metabolic, vascular and inflammatory processes, a hypothesis of metabotrophic factor deficit in the pathogenesis of adipose-linked diseases is discussed. Adipopharmacological evaluation of this hypothesis may provide novel targets for drug development.

The Cannabis sativa (marijuana) plant is well known for its mood regulating effects. Since the identification of two cannabinoid (CB) receptors for the plants major active constituent δ9-tetrahydrocannabinol (THC) around 1990, endogenous ligands, the endocannabinoids, have been discovered, leading to the definition of the ‘endocannabinoid-CBreceptor (ECBR) system’. The ligands, including anandamide and 2-arachidonylglycerol, are particularly interesting since they are derivatives of arachidonic acid, while interacting with related lipids such as oleoylethanolamide. During the previous decade, our knowledge and understanding of the ubiquitous presence and functions, as well as dysfunctions of the ECBR system has expanded dramatically. In the current review we will present an updated overview of the physiology, pathology and pharmacology of the ECBR system. Thus we will briefly describe its components (receptors, endocannabinoids, degradative enzymes). Next, we will discuss the involvement of the ECBR system in peripheral organ systems (gastrointestinal, immune, cardiovascular), brain (memory, movement, coordination, reward and addiction) as well as in pain and appetite-related systems. For example, CB1 and CB2 receptors mediate relaxation of the intestinal system and exert anti-inflammatory effects, while activating CB1 receptors enhances appetite and food intake and is critical for suckling in newborn mice. The third section will be devoted to the ECBR role in reproduction and perinatal development. Finally, pathophysiological issues and therapeutic potential will be discussed, based on the physiological functions ascribed to the ECBR system, such as cannabinoid-based therapies for irritable bowel disease, food-disorders and neuropsychiatric disturbances. Hopefully the next decade will witness its medicinal application of the ECBR system for the benefit of patients suffering from a variety of conditions.