- •Preface
- •Contents
- •1 Extracellular and Intracellular Signaling – a New Approach to Diseases and Treatments
- •1.1 Introduction
- •1.1.1 Linear Model of Drug Receptor Interactions
- •1.1.2 Matrix Model of Drug Receptor Interactions
- •1.2 Experimental Approaches to Disease Treatment
- •1.3 Adipokines and Disease Causation
- •1.4 Questions in Disease Treatment
- •1.5 Toxic Lifestyles and Disease Treatment
- •References
- •2.1 Introduction
- •2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion
- •2.3 Feedback between FA and the Adipocyte
- •2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue
- •2.8 Cell Heterogeneity in the Pancreatic Islet
- •2.16 Concluding Remarks
- •Acknowledgements
- •References
- •3 One Receptor for Multiple Pathways: Focus on Leptin Signaling
- •3.1 Leptin
- •3.2 Leptin Receptors
- •3.3 Leptin Receptor Signaling
- •3.3.4 AMPK
- •3.3.5 SOCS3
- •3.4 Leptin Receptor Interactions
- •3.4.1 Apolipoprotein D
- •3.4.2 Sorting Nexin Molecules
- •3.4.3 Diacylglycerol Kinase Zeta
- •3.4.4 Apolipoprotein J
- •References
- •4.1 Introduction
- •4.2 Leptin: A Brief Introduction
- •4.3 Expression of Leptin Receptors in Cardiovascular Tissues
- •4.6 Post Receptor Leptin Signaling
- •4.6.2 Mitogen Activated Protein Kinase Stimulation
- •4.7 Adiponectin
- •4.7.1 Adiponectin and Cardiovascular Disease
- •4.7.2 Adiponectin and Experimental Cardiac Hypertrophy
- •4.8 Resistin
- •4.8.1 Cardiac Actions of Resistin
- •4.8.1.1 Experimental Studies on the Cardiac Actions of Resistin
- •4.9 Apelin
- •4.9.1 Apelin and Heart Disease
- •4.10 Visfatin
- •4.11 Other Novel Adipokines
- •4.12 Summary, Conclusions and Future Directions
- •Acknowledgements
- •References
- •5 Regulation of Muscle Proteostasis via Extramuscular Signals
- •5.1 Basic Protein Synthesis
- •5.2.1 Hormones
- •5.2.1.1 Mechanisms of Action: Glucocorticoids
- •5.2.1.2 Mechanisms of Action: TH (T3)
- •5.2.1.3 Mechanisms of Action: Testosterone
- •5.2.1.4 Mechanisms of Action: Epinephrine
- •5.2.2 Local Factors (Autocrine/Paracrine)
- •5.2.2.1 Mechanisms of Action: Insulin/IGF Spliceoforms
- •5.2.2.2 Mechanisms of Action: Fibroblast Growth Factor (FGF)
- •5.2.2.3 Mechanisms of Action: Myostatin
- •5.2.2.4 Mechanisms of Action: Cytokines
- •5.2.2.5 Mechanisms of Action: Neurotrophins
- •5.2.2.7 Mechanisms of Action: Extracellular Matrix
- •5.2.2.8 Mechanisms of Action: Amino Acids (AA)
- •5.3 Regulation of Muscle Proteostasis in Humans
- •5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man
- •5.3.2 Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis
- •5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans
- •5.4.2 Disuse Atrophy
- •5.4.3 Sepsis
- •5.4.4 Burns
- •5.4.5 Cancer Cachexia
- •References
- •6 Contact Normalization: Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets
- •6.1 Introduction
- •6.2 Contact Normalization
- •6.3 Cadherins
- •6.4 Gap Junctions
- •6.5 Contact Normalization and Tumor Suppressors
- •6.6 Contact Normalization and Tumor Promoters
- •6.7 Conclusions
- •References
- •7.1 Introduction
- •7.2 Background on Migraine Headache
- •7.3 Migraine and Neuropathic Pain
- •7.4 Role of Astrocytes in Pain
- •7.5 Adipokines and Related Extracellular Signalling
- •7.6 The Future of Signaling Research to Migraine
- •Acknowledgements
- •References
- •8.1 Alzheimer’s Disease
- •8.1.2 Target for AD Therapy
- •8.2 AD and Metabolic Dysfunction
- •8.2.1 Impaired Glucose Metabolism
- •8.2.2 Lipid Disorders
- •8.2.3 Obesity
- •8.3 Adipokines
- •8.3.1 Leptin
- •8.3.2 Adiponectin
- •8.3.3 Resistin
- •8.3.4 Visfatin
- •8.3.5 Plasminogen Activator Inhibitor
- •8.3.6 Interleukin-6
- •8.4 Conclusions
- •References
- •9.1 Introduction
- •9.1.1 Structure and Function of Astrocytes
- •9.1.1.1 Morphology
- •9.1.1.2 Astrocyte Functions
- •9.1.2 Responses of Astrocytes to Injury
- •9.1.2.1 Reactive Astrocytosis
- •9.1.2.2 Cell Swelling
- •9.1.2.3 Alzheimer Type II Astrocytosis
- •9.2 Intracellular Signaling System in Reactive Astrocytes
- •9.2.1 Oxidative/Nitrosative Stress (ONS)
- •9.2.2 Protein Kinase C (PKC)
- •9.2.5 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3 Signaling Systems in Astrocyte Swelling
- •9.3.1 Oxidative/Nitrosative Stress (ONS)
- •9.3.2 Cytokines
- •9.3.3 Protein Kinase C (PKC)
- •9.3.5 Protein Kinase G (PKG)
- •9.3.7 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3.10 Ion Channels/Transporters/Exchangers
- •9.4 Conclusions and Perspectives
- •Acknowledgements
- •References
- •10.1 Adipokines, Toxic Lipids and the Aging Brain
- •10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids
- •10.1.2 Ceramide Toxicity in the Brain
- •10.3 Oxygen Radicals, Hydrogen Peroxide and Cell Death
- •10.4 Gene Transcription and DNA Damage
- •10.5 Conclusions
- •References
- •11.1 Introduction
- •11.2 Cellular Signaling
- •11.2.1 Types of Signaling
- •11.2.2 Membrane Proteins in Signaling
- •11.3 G Protein-Coupled Receptors
- •11.3.1 Structure of GPCRs
- •11.3.1.1 Structure Determination
- •11.3.1.2 Structural Diversity of Current GPCR Structures
- •11.3.1.3 Prediction of GPCR Structure and Ligand Binding
- •11.3.2 GPCR Activation: Conformation Driven Functional Selectivity
- •11.3.2.2 Ligand or Mutation Stabilized Ensemble of GPCR Conformations
- •11.3.2.4 GPCR Dimers and Interaction with Other Proteins
- •11.3.3 Functional Control of GPCRs by Ligands
- •11.3.3.1 Biased Agonism
- •11.3.3.2 Allosteric Ligands and Signal Modulation
- •11.3.4 Challenges in GPCR Targeted Drug Design
- •11.4 Summary and Looking Ahead
- •Acknowledgements
- •References
- •12.1 Introduction
- •12.5.1 Anthocyanins
- •12.5.2 Gallates
- •12.5.3 Quercetin
- •12.5.5 Piperine
- •12.5.6 Gingerol
- •12.5.7 Curcumin
- •12.5.8 Guggulsterone
- •12.6.1 Phytanic Acid
- •12.6.2 Dehydroabietic Acid
- •12.6.3 Geraniol
- •12.7 Agonists of LXR that Reciprocally Inhibit NF-jB
- •12.7.1 Stigmasterol
- •12.7.3 Ergosterol
- •12.8 Conclusion
- •References
- •13.1 Introduction
- •13.2 Selective Dopaminergic Neuronal Death
- •13.3 Signaling Pathways Involved in Selective Dopaminergic Neuronal Death
- •13.3.1 Initiators and Signaling Molecules
- •13.3.1.1 Response to Oxidative and Nitrosative Stress
- •13.3.1.2 Response to Altered Proteostasis
- •13.3.1.3 Response to Glutamate
- •13.3.1.4 Other Initiators
- •13.3.2 Signal Transducers, Intracellular Messengers and Upstream Elements
- •13.3.2.2 Small GTPases
- •13.3.3 Intracellular Signaling Cascades
- •13.3.3.1 Mitogen Activated Protein Kinases (MAPK) Pathway
- •13.3.3.2 PI3K/Akt Pathway
- •13.3.3.4 Unfolded Protein Response (UPR)
- •13.3.4 Potentially Involved Intracellular Signaling Components
- •13.3.4.3 PINK1
- •13.3.5.2 Dopamine Metabolism
- •13.3.5.3 Cell Cycle
- •13.3.5.4 Autophagy
- •13.3.5.5 Apoptosis
- •13.4 Conclusions
- •References
- •Subject Index
50 |
Chapter 3 |
di erent activities of leptin might be the result of di ering patterns of AMPK subunit expression in the various tissues, or of di erential expression of the AMPK activators LKB1, CaMKK or other possibilities.63
The mechanism by which leptin exerts its activities on AMPK activation are still unclear. However, several recent reports are uncovering these mechanisms. Uotani et al. have described that leptin activates AMPK in hepatic cells in a manner independent of phosphotyrosine residues of the long-form leptin receptor, whereas this mechanism involved a JAK2-dependent pathway.69 It has been reported that the absence of the protein tyrosine phosphatase 1B (PTP1B) at the hypothalamic level, which regulates JAK2 phosphorylation,70 increased leptin sensitivity by decreasing hypothalamic AMPK activity71 and increasing peripheral AMPK activity. Very recently it has also been reported that the activity of skeletal muscle AMPK parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice over-expressing leptin. Moreover it was further indicated that the activation of skeletal muscle AMPK was mediated by the hypothalamic melanocortin pathway.72 These results in turn revealed a complex mechanism for the regulation of peripheral leptinmediated AMPK activities, establishing a link between central and peripheral actions of leptin AMPK-mediated e ects.
3.3.5SOCS3
Finally, leptin receptor activation also recruits the suppressor of cytokine signaling 3 (SOCS3), a signaling protein involved in a negative feedback of leptin signal transduction.73 The SOCS3-mediated leptin signaling inhibition mechanism has been postulated by several studies. It was found that SOCS3 inhibits the leptin-induced tyrosine phosphorylation of JAK2 and co-precipitates with this protein in leptin-treated cell lysates.74 Indeed, it was also reported that SOCS3 mediated the inhibition of leptin signaling at the phosphotyrosine residue Tyr985, where SOCS3 was bound and consequently dampened STAT3 signaling.75 Also of note, SOCS3 expression is rapidly induced upon STAT3 activation, which is likely the main mechanism of leptin receptor self-regulation. Inhibition of phosphotyrosine residue Tyr1138, which is a binding site of the leptin receptor that elicits STAT3 recruitment, improved leptin receptor signaling inhibition caused by chronic stimulation.76
SOCS3 signaling has been related functionally to the establishment of leptin and insulin resistance.58,73 It has been described that reducing SOCS3 activity, by neuron-specific knockout or by global knockout, resulted in enhanced STAT3 expression and leptin-mediated weight-reducing e ects.77,78 Likewise, It has been reported that SOCS3 inhibited insulin signaling in the adipose tissue of obese mice (Figure 3.1).79
3.4 Leptin Receptor Interactions
Apart from the above-mentioned signaling pathways elicited by the leptin receptor, it is noteworthy that the leptin receptor also interacts with other
One Receptor for Multiple Pathways: Focus on Leptin Signaling |
51 |
proteins. These molecules may modulate leptin receptor signaling and introduce another piece of complexity in the generated signals.
3.4.1Apolipoprotein D
Apolipoprotein D (Apo D) is widely expressed in mammalian tissues with a remarkable expression at the central level (brain). This apolipoprotein, from a structural point of view, does not have a relevant similitude with other apolipoproteins. By contrast, Apo D has been considered a lipocalin, due to its structural homology with lipocalins, a family of lipid-binding proteins involved in the transport of lipids and small hydrophobic molecules. The functional relevance of this lipocalin is supported by the fact that genetic variants of Apo D are associated with abnormal lipid metabolism and increased risk of developing the metabolic syndrome.80 In line with this, it has been reported that Apo D and the leptin receptor are co-expressed in neurons of the hypothalamic arcuate and paraventricular nuclei, two brain areas that are known to be involved in food intake and body-weight regulation. Moreover, it has also been described, in the same study, that Apo D interacted specifically with the cytoplasmic portion of the long-form leptin receptor, but not with the short form Ob-Ra.81 All together, these data suggested that Apo D may be involved in leptin receptor signaling and consequently in its functions such as bodyweight regulation and energy homeostasis.
3.4.2Sorting Nexin Molecules
The sorting nexins (SNXs) are a family of PX domain-containing proteins widely expressed in mammalian tissues. Despite their hydrophilic nature, the sorting nexins are found partially associated with cellular membranes. SNXs have been suggested to be involved in pro-degradative sorting, internalization, endosomal recycling, or simply in endosomal sorting.82 Among the large family of sorting nexins, several sorting nexins, such as SNX1, SNX2, SNX4 and SNX6, have been co-immunoprecipitated with receptors with tyrosine kinase activity, like endothelial growth factor receptor EGFR, plateletderived growth factor receptor and insulin receptor.83,84 Intriguingly, these
sorting nexins were also associated with the leptin receptor long form, but not with the short or medium isoforms.83,84 As a whole, these data suggest
that sorting nexins might control leptin receptor tra cking by means of its intracellular region and, consequently, this interaction could also control leptin receptor signaling.
3.4.3Diacylglycerol Kinase Zeta
Diacylglycerol kinases (DGKs) are involved in the regulation of intracellular levels of diacylglycerol and phosphatidic acid, as well as in the synthesis of triacylglycerols.85 Among these kinases there is diacylglycerol kinase zeta (DGKz), which is characterized by its four C-terminal ankyrin repeats and is