Brain insulin: regulation,mechanisms of action and functions

1. While many questions remain unanswered, it is now well documented that, contrary to earlier views, insulin is an important neuromodulator, contributing to neurobiological processes, in particular energy homeostasis and cognition. A specific role on cognitive functions related to feeding is proposed, and it is suggested that brain insulin from different sources might be involved in the above vital functions in health and disease.2. A molecule identical to pancreatic insulin, and specific insulin receptors, are found widely distributed in the central nervous system networks related to feeding, reproduction, or cognition.3. The actions of insulin in the central nervous system may be under both multilevel and multifactorial controls. The amount of blood insulin reaching the brain, brain insulin stores and secretion, potential local biosynthesis and degradation of the peptide, and insulin receptors and signal transduction can be affected by metabolic factors induced by nutrients, hormones, neurotransmitters, and regulatory peptides, peripherally or in the central nervous system.4. Glucose and serotonin regulate insulin directly in the hypothalamus and may be of importance for its biological effects. Central mechanisms regulating glucose-induced insulin secretion show some analogy with the mechanisms operating in the pancreas.5. A cross-talk between insulin and leptin receptors has been observed in the brain, and a regulation of central insulin actions, potentially via serotonin modulation, by leptin, galanin, melanocortins, and neuropeptide Y (NPY) is suggested.6. A more complete knowledge of the biological role of insulin in brain function and dysfunction, and of the regulatory mechanisms involved in these processes, constitutes a real advancement in the understanding of the pathophysiology of metabolic and mental diseases and could lead to important medical benefits.     

To SIR with Polycomb: linking silencing mechanisms

Yeast SIR2, the most evolutionarily conserved deacetylase, plays an essential role in epigenetic silencing at the silent mating type loci and telomeres. SIR2 has been implicated in chromatin silencing and lifespan determination in several organisms. Discovery that Drosophila SIR2 is also involved in epigenetic silencing mediated by the Polycomb group proteins and is physically associated with a complex containing the E(Z) histone methyltransferase has wide implications. These findings suggest possible link of Polycomb system to diverse cellular processes including senescence.     

Escape behavior: linking neural computation to action

A new study uses a combination of physiological and optogenetic techniques to identify visual neurons in fruit flies that detect approaching objects, and whose activation is integral in escaping an oncoming threat.     

Neural circuit mechanisms linking courtship and reward in Drosophila males

1. Download : Download high-res image (234KB)
2. Download : Download full-size image

     

Brain mechanisms underlying flavour and appetite

Complementary neurophysiological recordings in macaques and functional neuroimaging in humans show that the primary taste cortex in the rostral insula and adjoining frontal operculum provides separate and combined representations of the taste, temperature and texture (including viscosity and fat texture) of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in the orbitofrontal cortex, these sensory inputs are for some neurons combined by learning with olfactory and visual inputs. Different neurons respond to different combinations, providing a rich representation of the sensory properties of food. In the orbitofrontal cortex, feeding to satiety with one food decreases the responses of these neurons to that food, but not to other foods, showing that sensory-specific satiety is computed in the primate (including human) orbitofrontal cortex. Consistently, activation of parts of the human orbitofrontal cortex correlates with subjective ratings of the pleasantness of the taste and smell of food. Cognitive factors, such as a word label presented with an odour, influence the pleasantness of the odour and the activation produced by the odour in the orbitofrontal cortex. These findings provide a basis for understanding how what is in the mouth is represented by independent information channels in the brain; how the information from these channels is combined; and how and where the reward and subjective affective value of food is represented and is influenced by satiety signals. Activation of these representations in the orbitofrontal cortex may provide the goal for eating, and understanding them helps to provide a basis for understanding appetite and its disorders.     

Phenotypic plasticity: linking molecular mechanisms with evolutionary outcomes

We argue that phenotypic plasticity should be broadly construed to encompass a diversity of phenomena spanning several hierarchical levels of organization. Despite seemingly disparate outcomes among different groups of organisms (e.g., the opening/closing of stomata in leaves, adjustments of allocation to growth/reproduction, or the production of different castes in social insects), there are underlying shared processes that initiate these responses. At the most fundamental level, all plastic responses originate at the level of individual cells, which receive and process signals from their environment. The broad variations in physiology, morphology, behavior, etc., that can be produced by a single genotype, can be accounted for by processes regulating gene expression in response to environmental variation. Although evolution of adaptive plasticity may not be possible for some types of environmental signals, in many cases selection has molded responses to environmental variation that generate precise and repeatable patterns of gene expression. We highlight the example of responses of plants to variation in light quality and quantity, mediated via the phytochrome genes. Responses to changes in light at particular stages of plants' life cycles (e.g., seed germination, competition, reproduction) are controlled by different members of this gene family. The mechanistic details of the cell and molecular biology of phytochrome gene action (e.g., their effects on expression of other genes) is outlined. Plasticity of cells and organisms to internal and external environmental signals is pervasive, and represents not just an outcome of evolutionary processes, but also a potentially important molder of them. Phenotypes originally initiated via a plastic response, can be fixed through genetic assimilation as alternate regulatory pathways are shut off. Evolution of mechanisms of plasticity and canalization can both reduce genetic variation, as well as shield it. When the organism encounters novel environmental conditions, this shielded variation may be expressed, revealing hidden reaction norms that represent the raw material for subsequent evolution.     

低氧预适应的脑机制

A concept ot tissue adaptation to hypoxia( i.e. hypoxic preconditioning) was developed and its corresponding animal models were reproduced in 1966s. The methods of model reproduction in rat, rabbit, and mouse in particular and the main results are brifly introduced in this review. The tolerance to hypoxia o{ preconditioned animals is significantly increased. Regular changes in animals‘ behavior, neurophysiology, respiratory and circulatory physiology, neuromorphology in vivo and {unction of brain and spinal cord in vitro are briefly demonstrated. The protective effects in vivo and in vitro of homogenate extract taken from the brain o{ preconditioned animals, neurochemcals and molecular neurobiolcgical alterations are briefly presented. The essence and significance of tissue adaption to hypoxia/hypoxic preconditioning are discussed in the review in terms of evolution and practical implication.     

Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation

Geranylgeranyl diphosphate is a 20-carbon isoprenoid phospholipid whose lipid moiety can be post-translationally incorporated into proteins to promote membrane association. The process of geranylgeranylation has been implicated in anti-proliferative effects of clinical agents that inhibit enzymes of the mevalonate pathway (i.e. statins and nitrogenous bisphosphonates) as well as experimental agents that deplete geranylgeranyl diphosphate. Inhibitors of geranylgeranyl diphosphate synthase are an attractive way to block geranylgeranylation because they possess a calcium-chelating substructure to allow localization to bone and take advantage of a unique position of the enzyme within the biosynthetic pathway. Here, we describe recent advances in geranylgeranyl diphosphate synthase expression and inhibitor development with a particular focus on the molecular mechanisms that link geranylgeranyl diphosphate to cell proliferation via geranylgeranylated small GTPases.     

Brain mechanisms in normal and dyslexic readers

Developmental dyslexics, individuals with an unexplained difficulty reading, have been shown to have deficits in phonological processing -- the awareness of the sound structure of words -- and, in some cases, a more fundamental deficit in rapid auditory processing. In addition, dyslexics show a disruption in white matter connectivity between posterior and frontal regions. These results give continued support for a neurobiological etiology of developmental dyslexia. However, more research will be required to determine the possible causal relationships between these neurobiological disruptions and dyslexia.     

Cortical mechanisms and cues for action

Monkeys have more highly developed brains and are more intelligent than rats; yet rats learn some tasks as efficiently as monkeys. For example, rats are as quick at discovering which of two doors hides food or how to open the doors. Presumably tasks of this sort do not greatly tax cortical associative mechanisms since the animals have only to cumulate facts about objects. It is argued that cortical mechanisms are crucial for the ability to relate together information that is presented at different times or in different places. After removal of parts of frontal cortex monkeys can still associate cues that are presented together but they are poor at relating cues that are presented apart.     

Sphingosylphosphorylcholine-biological functions and mechanisms of action

Compared to the lysophospholipid mediators, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), little information is available regarding the molecular mechanisms of action, metabolism and physiological significance of the related sphingosylphosphorylcholine (SPC). S1P and LPA have recently been established as agonists at several G-protein-coupled receptors of the EDG family, S1P additionally serves an intracellular second messenger function. Several cellular effects of SPC can be explained by low-affinity binding to and activation of S1P-EDG receptors. However, certain cellular and subcellular actions of SPC are not shared by S1P, suggesting that SPC, which has been identified in normal blood plasma, ascites and various tissues, is a lipid mediator in its own right. This concept was corroborated by the recent discovery of specific high-affinity G-protein-coupled SPC receptors. In this article, our present knowledge on cellular actions and biological functions of SPC will be reviewed.     

Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B

The sphingolipid ceramide negatively regulates insulin action by inhibiting Akt/protein kinase B (PKB), a serine/threonine kinase that is a central regulator of glucose uptake and anabolic metabolism. Despite considerable attention, the molecular mechanism accounting for this action of ceramide has remained both elusive and controversial. Herein we utilized deletion constructs encoding two different functional domains of Akt/PKB to identify which region of the enzyme conferred responsiveness to ceramide. Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt/PKB by two independent mechanisms. First, using the isolated pleckstrin homology domain, we found that ceramide specifically blocks the translocation of Akt/PKB, but not its upstream activator phosphoinositide-dependent kinase-1, to the plasma membrane. Second, using a construct lacking this pleckstrin homology domain, which does not require translocation for activation, we found that ceramide stimulates the dephosphorylation of Akt/PKB by protein phosphatase 2A. Collectively these findings identify at least two independent mechanisms by which excessive ceramide accumulation in peripheral tissues could contribute to the development of insulin resistance. Moreover the results obtained provide a unifying theory to account for the numerous dissenting reports investigating the actions of ceramide toward Akt/PKB.     

Biochemical mechanisms of fluorine action

Biochemical mechanisms of fluorine ion action accounting for the biological role and significance of fluorine for vital activity of the organism are investigated. Results of these investigations are generalized. This trace element is shown to participate at least in two vitally important systems of the organism: the adenylate cyclase system which accounts for the cell response to neuroendocrinological information and the immune protection system providing antimicrobic resistance. Available data permit considering that cytotoxic fluorine action is based on the ability to hinder protein synthesis in eukaryotes and to stimulate peroxidation processes of biomembrane lipids. Inorganic fluorine compounds are recommended to be used with the treatment-and-prophylactic purpose for certain pathologic states, associated with its insufficient or excessive arrival into the organism.