Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 4, Issue 2, 2004

Overweight and obesity are associated with increased risk of a number of clinically important chronic conditions such as, Type 2 diabetes and several risk factors for coronary heart disease (CHD): atherosclerosis, hypertension, hyperlipidemia, arteriosclerosis. Obesity results from an imbalance between energy intake and expenditure. Generally, anti-obesity pharmacotherapy targets both reduction of energy intake and increase of energy expenditure. Due to several associated abnormalities, it is now considered that an anti-obesity agent which not only reduce weight, but also improve metabolic and cardiovascular functions will have better therapeutic potential. Peroxisome proliferators-activated receptors (PPARs), are lipid activated transcription factors that control carbohydrate and lipid homeostasis. The PPAR subfamily of nuclear receptors comprises three isoforms - PPARα, PPARγ and PPARδ. PPARα is predomionantly involved in fatty acid catabolism, whereas PPARγ promotes lipid storage and triggers cellular differentiation and insulin sensitization. Dual activation of PPARα and γ controls glucose homeostasis, insulin sensitization and lipid metabolism, In addition, PPARα and g activation is also known to exert anti-inflammatory action, exert direct actions for modulating the vascular endothelial functions and thereby showing anti-hypertensive activity. Here we have reviewed the diverse pieces of evidence linking obesity with PPARs and how selective manipulation of PPAR isoforms by agonists or antagonists can potentially lead to the discovery of new drugs to treat weight gain and the related complications.

The prevalence of obesity has increased in alarming proportions over the past 10 years and being recognized as an epidemic. Obesity is now considered as a disease, and is associated with insulin resistance. This follows a wide array of pathophysiological sequelae including type 2 diabetes, hypertension, hyperlipidemia, and atherosclerosis, collectively referred to as metabolic syndrome or syndrome X. The increased numbers of mortality and morbidity from obesity-related complications like diabetes and cardiovascular diseases have raised serious concern. Despite the growing understanding of biologic pathways underlying feeding behavior and metabolic disorders leading to weight gain and eventually obesity, a proportional success has not been achieved in terms of drug discovery to combat the obesity epidemic. Several approaches like appetite control, inhibition of dietary fat absorption, insulin and leptin revival, inhibition of fat synthesis, and increased fat mobilization and burning, have been known to develop therapies to treat obesity. These biologic pathways are carried out by a number of players in a tissue-specific manner. Recent studies using knockouts and transgenics have further identified and validated several molecular targets directly involved in the pathogenesis of obesity. However, despite the plethora of research data in the obesity arena and validated biologic targets, a blockbuster drug is yet to hit the market. This review discusses the importance of major tissues and proteins in the pathogenesis of obesity, and ways to combat obesity by modulating these players.

Obesity is an epidemic in the United States and worldwide. Although the personal, societal, and economic costs of this disorder are staggering, the medical research community has yet to develop definitive therapies. Progress has been made in understanding basic processes that underlie normal regulation of body adipose stores. However, mechanisms that account for the majority of human obesity have yet to be identified. Based upon current models of body weight regulation, the hypothesis is discussed herein that hypothalamic responses to “adiposity signals uo; such as insulin and leptin are disrupted in the setting of obesity. Recent work has determined specific mechanisms by which insulin and leptin normally act in the CNS and we will present mechanistic hypotheses for the development of resistance to these hormones. Furthermore, results of several macronutrient-based dietary intervention studies will be presented within the context of this model. Finally, we will discuss an emerging area that suggests that rewarding aspects per se of foods may contribute to the pathophysiology of obesity.

During the past two decades, the prevalence of obesity has greatly risen worldwide. These changes have occurred among genetically stable populations, indicating that modifications of behavioral factors like dietary and physical activity must underlie the recent obesity epidemic. However, genetic factors undoubtedly have a great effect on individual predisposition, since 25 to 80 percent of the variation in body-mass index is heritable. Eating behavior, disordered eating behaviors and food preferences are in part heritable, and a family history of overeating is more frequent in obese individuals with binge-eating disorder than in the general population. The identification of genes causing both syndromic (Prader Willi) and rare monogenic (leptin / melanocortin pathways) forms of obesity, highlight the importance of genetic determinants in obesity. The common forms of obesity are, however, polygenic, and could modestly modulate behavior component. The recent identification of GAD2 gene variations modulating food intake and increasing the risk for severe obesity highlights the role of the GABA pathway in eating behavior. Other pathways involved in behavior, including Dopamine, serotonin and cannabinoid pathways are candidate for obese susceptibility genes. Modest individual effects of already identified at risk variants for abnormal food intake, may be amplified by gene-gene and geneenvironment interactions.

Genetic obesity syndromes in mouse and man have led to an appreciation of a neural network of interacting, phenotypically distinct, neurons in the hypothalamus that are important for the central regulation of appetite and body weight. The network is composed of leptin-sensitive neurons that express either the agonist or antagonist of the melanocortin-4 receptor (MC4R) on the MC4R-expressing neurons. The inter- and intraneuronal signaling that occurs in this network of “obesity neurons” is reviewed and a new approach is described for the mining of these neurons for novel anti-obesity drug targets.

Vitamin A is an essential micronutrient in vertebrates throughout embryogenesis and fetal differentiation and growth, postnatal development, adulthood and aging, either during normal physiological conditions or in some pathological cases, principally in several neoplasias. Vitamin A is a generic designation for all compounds, natural or synthetic, with most, but not necessaily all, properties of all-trans-retinol compounds. In order to fulfill all of its functions, the different forms of retinoids must be metabolized to its principal active biological compound, retinoic acid, which functions as a ligand controlling retinoic acid pathway through retinoid acid receptors (RARs and RXRs), which binds, to DNA retinoid acid response elements (RAREs), thus regulating, directly or interacting with several others factors, the transcription of innumerous genes. The aim of this review is primarily to discuss and summarize the homeostasis of retinoids, from their absorption and storage, to the genetic signal transduction of retinoic acid. An attempt to integrate the most pertinent and recent information available from different studies, with an emphasis on new insights into the several metabolic pathways of retinoids and also in the role of retinoic acid as a regulatory factor of transcription, is made.

The purpose of this review is to summarize the current knowledge of the biochemical activities and the potential cellular source(s) of the inflammatory marker procalcitonin (PCT). PCT has been proven to be a reliable indicator for the diagnosis of sepsis. Since serum-PCT concentrations correlate with the severity of the disease, routine PCT measurements became of prognostic value for the monitoring of septic patients. This correlation supports the concept that PCT exhibits detrimental effects within the host organism (e.g. via contribution to the deleterious fall in blood pressure observed in the advanced state of sepsis). However, no precise information is available to date concerning PCT's mode of action and its cellular origin during the inflammatory process. In recent studies, we could show that PCT affects the generation of nitric oxide (NO) and tumor necrosis factor-α (TNF). Both NO and TNF-α are markedly elevated in the plasma of septic patients and it is suggested that they play a role as mediators or modulators for the onset of septic shock. It is imminent to further investigate the role of PCT within the inflammatory cascade, its effects on other inflammatory agonists as well as to gain further insight into the signal transduction mechanisms following cellular activation by PCT. The characterization of PCT with respect to its origin and its biochemical functions will provide further insight into the pathogenesis of sepsis and septic shock, and detailed knowledge of PCT's mode of action are an essential prerequisite for potential therapeutical interventions directed towards PCT metabolism.