Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume 4, No. 2, 2004
Contents
Obesity
Guest
Editor: R.A.K. Srivastava
The Role of PPARs in Obesity and other
Insulin Resistance Associated Disorders Pp.67-73
R.
Chakrabarti and R. Rajagopalan
Search for Obesity Drugs: Targeting Central
and Peripheral Pathways Pp.75-90
Rai
Ajit K Srivastava and Neelam Srivastava
The Human Obesity Epidemic - A Physiological
Perspective Pp.91-104
K.D.
Niswender, D.J. Clegg, C.D. Morrison, G.J. Morton and S.C. Benoit
Obesity: Genetics, Behavior or a Combination
of Both Pp.105-111
David
Meyre, Philippe Boutin, and Philippe Froguel
Signaling in “Obesity Neurons” Pp.113-117
Robert
G. MacKenzie
Metabolic Pathways and Modulating Effects of
Vitamin A Pp.119-142
Paula
Rodrigues, Carlos Gonçalves, and Vasco Bairos
The Role of Procalcitonin in Sepsis and
Septic Shock Pp.143-147
Georg
Hoffmann
Abstracts
[Back to top] The Role of PPARs in Obesity and other
Insulin Resistance Associated Disorders
R.
Chakrabarti and R. Rajagopalan
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 – PPARa, PPARg and
PPARd.
PPARa
is predomionantly involved in fatty acid catabolism, whereas PPARg
promotes lipid storage and triggers cellular differentiation and insulin
sensitization. Dual activation of PPARa and g
controls glucose homeostasis, insulin sensitization and lipid metabolism, In
addition, PPARa
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.
[Back to top] Search for Obesity Drugs: Targeting Central
and Peripheral Pathways
Rai
Ajit K Srivastava and Neelam Srivastava
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.
[Back to top] The Human Obesity Epidemic - A Physiological
Perspective
K.D.
Niswender, D.J. Clegg, C.D. Morrison, G.J. Morton and S.C. Benoit
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” 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.
[Back to top] Obesity: Genetics, Behavior or a Combination
of Both
David
Meyre, Philippe Boutin, and Philippe Froguel
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 gene-environment
interactions.
[Back to top] Signaling in “Obesity Neurons”
Robert
G. MacKenzie
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.
[Back to top] Metabolic Pathways and Modulating Effects of
Vitamin A
Paula Rodrigues, Carlos Goncalves, and Vasco Bairos
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.
[Back to top] The Role of Procalcitonin in Sepsis and
Septic Shock
Georg Hoffmann
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-a (TNF). Both NO and TNF-a 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.