Leptin signaling in breast cancer: an overview

The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.     

The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response

A key role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities.     

The endocannabinoid signaling system: a marriage of PUFA and musculoskeletal health

The role of diet in health and diseases related to muscle and bone has been an area of active study. Recently, endocannabinoids (EC), endogenous derivatives of arachidonic acid, an omega-6 (n-6) polyunsaturated fatty acid (PUFA), have been discovered to play regulatory roles in bone mass and muscle energy metabolism. This signaling system consists of the G-protein coupled cannabinoid receptors, CB1 and CB2, expressed in central and peripheral tissues and cells, which are variably activated by the production and on demand release of endogenous and synthetic agonists and antagonists. We propose that the balance between omega-6 and omega-3 (n-3) PUFA is an important modifier for the activation and suppression of endocannabinoid receptors and therefore, downstream signaling actions in cells. The potential of dietary PUFA to regulate this signaling system to influence the metabolic and physiological outcomes favorable to musculoskeletal health is the purpose of this review. The important role of n-3 PUFA in metabolic and physiological processes that attenuate muscle and bone loss under conditions of disease and stress is one aspect described herein. In this review, we first introduce the EC agonists (ligands) and their receptors (CB1 and CB2) and the general actions of EC signaling in various organs and systems. Second, we describe EC signaling in bone and muscle and how dietary PUFA influence the levels of endogenous agonists. Third, we discuss the potential implications of how dietary PUFA impact this system to minimize muscle atrophy and osteopenia and support healthy muscle development and bone modeling.     

Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit

Recently developed therapeutics for obesity, targeted against cannabinoid receptors, result in decreased appetite and sustained weight loss. Prior studies have demonstrated CB1 receptors (CB1Rs) and leptin modulation of cannabinoid synthesis in hypothalamic neurons. Here, we show that depolarization of perifornical lateral hypothalamus (LH) neurons elicits a CB1R-mediated suppression of inhibition in local circuits thought to be involved in appetite and "natural reward." The depolarization-induced decrease in inhibitory tone to LH neurons is blocked by leptin. Leptin inhibits voltage-gated calcium channels in LH neurons via the activation of janus kinase 2 (JAK2) and of mitogen-activated protein kinase (MAPK). Leptin-deficient mice are characterized by both an increase in steady-state voltage-gated calcium currents in LH neurons and a CB1R-mediated depolarization-induced suppression of inhibition that is 6-fold longer than that in littermate controls. Our data provide direct electrophysiological support for the involvement of endocannabinoids and leptin as modulators of hypothalamic circuits underlying motivational aspects of feeding behavior.     

Presynaptic specificity of endocannabinoid signaling in the hippocampus

Endocannabinoids are retrograde messengers released by neurons to modulate the strength of their synaptic inputs. Endocannabinoids are thought to mediate the suppression of GABA release that follows depolarization of a hippocampal CA1 pyramidal neuron-termed "depolarization-induced suppression of inhibition" (DSI). Here, we report that DSI is absent in mice which lack cannabinoid receptor-1 (CB1). Pharmacological and kinetic evidence suggests that CB1 activation inhibits presynaptic Ca2+ channels through direct G protein inhibition. Paired recordings show that endocannabinoids selectively inhibit a subclass of synapses distinguished by their fast kinetics and large unitary conductance. Furthermore, cannabinoid-sensitive inputs are unusual among central nervous system synapses in that they use N- but not P/Q-type Ca2+ channels for neurotransmitter release. These results indicate that endocannabinoids are highly selective, rapid modulators of hippocampal inhibition.     

Comparative biology of the endocannabinoid system possible role in the immune response.

In this review we discuss data showing that the endogenous cannabinoid system, represented by cannabinoid receptors, endogenous cannabinoid receptor ligands and enzymes for the biosynthesis and degradation of these ligands, is conserved throughout evolution from coelenterates to man. This signaling system has been suggested to play several roles in animals, including the regulation of cell development and growth, nervous functions, reproduction and feeding behavior. In this article, however, we shall describe with more detail the possible function of the endogenous cannabinoid system in the modulation of immune response in organisms from the lower to the higher levels of animal evolution.     

The endocannabinoid system: a physiological perspective on its role in psychomotor control

The discovery of cannabinoid receptors has led to the identification of two natural activators for these receptors, anandamide and 2-arachidonoylglycerol, and to the elucidation of their biochemical pathways of formation and inactivation. Although the physiological significance of the endogenous cannabinoid system is still poorly understood, important information is becoming available on the possible functional roles of this system in the basal ganglia, a forebrain region that is involved in the control of sensorimotor and motivational aspects of behavior. These discoveries - which are going to enrich the way in which we look at basal ganglia functions - are summarized in this mini-review. The role of the endocannabinoids as modulators of psychomotor behaviors and the potential therapeutic perspectives deriving from the pharmacological manipulation of the endogenous cannabinoid system are also discussed.     

Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system

The medicinal properties of exogenous cannabinoids have been recognized for centuries and can largely be attributed to the activation in the nervous system of a single G-protein-coupled receptor, CB1. However, the beneficial properties of cannabinoids, which include relief of pain and spasticity, are counterbalanced by adverse effects such as cognitive and motor dysfunction. The recent discoveries of anandamide, a natural lipid ligand for CB1, and an enzyme, fatty acid amide hydrolase (FAAH), that terminates anandamide signaling have inspired pharmacological strategies to augment endogenous cannabinoid ('endocannabinoid') activity with FAAH inhibitors, which might exhibit superior selectivity in their elicited behavioral effects compared with direct CB1 agonists.     

Epigenetics in the nervous system: An overview of its essential role

The role that epigenetic mechanisms play in phenomena such as cellular differentiation during embryonic development, X chromosome inactivation, and cancers is well-characterized. Epigenetic mechanisms have been implicated to be the mediators of several functions in the nervous system such as in neuronal-glial differentiation, adult neurogenesis, the modulation of neural behavior and neural plasticity, and also in higher brain functions like cognition and memory. Its particular role in explaining the importance of early life/social experiences on adult behavioral patterns has caught the attention of scientists and has spawned the exciting new field of behavioral epigenetics which may hold the key to explaining many complex behavioral paradigms. Epigenetic deregulation is known to be central in the etiology of several neuropsychiatric disorders which underscore the importance of understanding these mechanisms more thoroughly to elucidate novel and effective therapeutic approaches. In this review we present an overview of the findings which point to the essential role played by epigenetics in the vertebrate nervous system.     

Biological applications of the SAS system: an overview

The SAS system provides biologists with a flexible, easy touse software package for data analysis. Through a combinationof data management tools, a wide variety of pre-programmed proceduresfor sorting, graphing, and statistical analysis and a sophisticatedprogramming language, SAS software can perform all analyticalneeds for most problems. The recent availability of SAS softwareon mainframes other than IBM, and more recently on the microcomputer,means that most scientists can have access to the software.In this review we discuss the structure of the SAS languageand demonstrate its power in the analysis of biological problems.Although to a lesser extent now than originally, the SAS systemis statistically oriented and a working knowledge of statisticsis recommended before using its statistical capabilities. However,all biologists will find its data management and summarizationcapabilities very useful. Received on September 9, 1987; accepted on September 17, 1987     

Evolution of the mitochondrial genetic system: an overview

Mitochondria, semi-autonomous organelles possessing their own genetic system, are commonly accepted to descend from free-living eubacteria, namely hydrogen-producing alpha-proteobacteria. The progressive loss of genes from the primitive eubacterium to the nucleus of the eukaryotic cell is strongly justified by the Muller rachet principle, which postulates that asexual genomes, like mitochondrial ones, accumulate deleterious and sublethal mutations faster than sexual genomes, like the nucleus. According to this principle, the mitochondrial genome would be doomed to death; instead, we observe that the mitochondrial genome has a variable size and structure in the different organisms, though it contains more or less the same set of genes. This is an example of genetic conservation versus structural diversity. From an evolutionary point of view the genetic system of organelles is clearly under strong selective pressure and for its survival it needs to utilize strategies to slow down or halt the ratchet. Anyway, the mitochondrial genome changes with time, and the rate of evolution is different for both diverse regions of the mtDNA and between lineages, as demonstrated in the case of mammalian mt genomes. We report here our data on the evolution of the mitochondrial DNA in mammals which demonstrate the suitability of mtDNA as a molecular tool for evolutionary analyses.     

DNA fingerprinting in the criminal justice system: an overview

DNA fingerprinting is a powerful technology that has revolutionized forensic science. No two individuals can have an identical DNA pattern except identical twins. Such DNA-based technologies have enormous social implications and can help in the fight against crime. This technology has experienced many changes over time with many advancements occurring. DNA testing is a matter of serious concern as it involves ethical issues. This article describes various trends in DNA fingerprinting and the current technology used in DNA profiling, possible uses and misuses of DNA databanks and ethical issues involved in DNA testing. Limitations and problems prevailing in this field are highlighted.     

Occurrence and possible biological role of the endocannabinoid system in the sea squirt Ciona intestinalis

A cannabinoid receptor orthologue (CiCBR) has been described in the sea squirt Ciona intestinalis. Here we report that CiCBR mRNA expression is highest in cerebral ganglion, branchial pharynx, heart and testis of C. intestinalis, and that this organism also contains cannabinoid receptor ligands and some of the enzymes for ligand biosynthesis and inactivation. Using liquid chromatography-mass spectrometry, the endocannabinoid anandamide was found in all tissues analysed (0.063-5.423 pmol/mg of lipid extract), with the highest concentrations being found in brain and heart. The endocannabinoid 2-arachidonoylglycerol (2-AG) was fivefold more abundant than anandamide, and was most abundant in stomach and intestine and least abundant in heart and ovaries (2.677-50.607 pmol/mg of lipid extract). Using phylogenomic analysis, we identified orthologues of several endocannabinoid synthesizing and degrading enzymes. In particular, we identified and partly sequenced a fatty acid amide hydrolase (FAAH) orthologue, showing 44% identity with human FAAH and containing nearly all the amino acids necessary for a functional FAAH enzyme. Ciona intestinalis also contained specific binding sites for cannabinoid receptor ligands, and an amidase enzyme with pH-dependency and subcellular/tissue distribution similar to mammalian FAAHs. Finally, a typical C. intestinalis behavioural response, siphon reopening after closure induced by mechanical stimulation, was inhibited by the cannabinoid receptor agonist HU-210, and this effect was significantly attenuated by mammalian cannabinoid receptor antagonists.     

The endocannabinoid system in neurodegeneration

Endocannabinoids are bioactive lipids, that comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied endocannabinoids, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol, the psychoactive principle of hashish and marijuana. It is known that the activity of endocannabinoids at their receptors is limited by cellular uptake through specific membrane transporters, followed by intracellular degradation by a fatty acid amide hydrolase (for AEA and partly 2-AG) or by a monoacylglycerol lipase (for 2-AG). Together with AEA, 2-AG and congeners, the proteins that bind, transport and metabolize these lipids form the "endocannabinoid system". This new system will be briefly presented in this review, in order to put in a better perspective the role of the endocannabinoid pathway in neurodegenerative disorders, like Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of endocannabinoid receptors, or of inhibitors of endocannabinoid metabolism, as next-generation therapeutics will be discussed.     

Genetic polymorphisms of the endocannabinoid system

Disturbances in the endocannabinoid system has been linked to diseases and conditions such as Parkinson's, schizophrenia, pain, energy metabolism, immune modulation, and bone density. Since the early 1990s, a number of genetic polymorphisms in the genes and proteins of the endocannabinoid system have been characterized. Currently identified genetic polymorphisms of the endocannabinoid system are reviewed here with particular consideration given to polymorphisms linked to drug and alcohol abuse, schizophrenia, other mental disorders, and energy metabolism.     

The endocannabinoid system in invertebrates

What is the role of the cannabinoid system in invertebrates and can it tell us something about the human system? We discuss in this review the possible presence of the cannabinoid system in invertebrates. Endocannabinoid processes, i.e., enzymatic hydrolysis, as well as cannabinoid receptors and endocannabinoids, have been identified in various species of invertebrates. These signal molecules appear to have multiple roles in invertebrates; diminishing sensory input, control of reproduction, feeding behavior, neurotransmission and antiinflammatory actions. We propose that since this system worked so well, it was retained during evolution, and that invertebrates can serve as a model to study endogenous cannabinoid signaling.     

Role of the endocannabinoid system in Alzheimer's disease: new perspectives

The role of the endocannabinoid system in several diseases is currently under intense study. Among these, Alzheimer's disease may be a new promising area of research. We have recently reported the existence of profound changes in the location and density of several elements of this system in Alzheimer's disease tissue samples, indicating that a non-neuronal endocannabinoid system is up-regulated in activated glia. Additional data from other groups suggest that glial cells may be important elements in the regulation of endocannabinoid system activity, both in health as in disease. Some of these aspects are briefly discussed in the present review.