Regulation of bone remodeling by the central and peripheral nervous system

The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo. Following initial studies reporting the presence of nerves and nerve-derived products within the bone microenvironment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling. The function of a number of “osteo-neuromediators” has been characterized, including norepinephrine and the beta2-adrenergic receptor, Neuropeptide Y and the Y1 and Y2 receptors, endocannabinoids and the CB1 and CB2 receptors, as well as dopamine, serotonin and their receptors and transporters, Calcitonin gene-related peptide, and neuronal NOS. This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling. The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and how bone cells signal back to central centers, because the definition of a homeostatic function implies the existence of feedback signals. Together, these findings shed a new light on the complexity of the mechanisms regulating bone remodeling and uncovered new potential therapeutic strategies for the design of bone anabolic treatments. This review summarizes the latest advances in this area, focusing on investigations based on in vivo animal studies.     

Regulation of autophagy and mitophagy by nutrient availability and acetylation

Normal cellular function is dependent on a number of highly regulated homeostatic mechanisms, which act in concert to maintain conditions suitable for life. During periods of nutritional deficit, cells initiate a number of recycling programs which break down complex intracellular structures, thus allowing them to utilize the energy stored within. These recycling systems, broadly named “autophagy”, enable the cell to maintain the flow of nutritional substrates until they can be replenished from external sources. Recent research has shown that a number of regulatory components of the autophagy program are controlled by lysine acetylation. Lysine acetylation is a reversible post-translational modification that can alter the activity of enzymes in a number of cellular compartments. Strikingly, the main substrate for this modification is a product of cellular energy metabolism: acetyl-CoA. This suggests a direct and intricate link between fuel metabolites and the systems which regulate nutritional homeostasis. In this review, we examine how acetylation regulates the systems that control cellular autophagy, and how global protein acetylation status may act as a trigger for recycling of cellular components in a nutrient-dependent fashion. In particular, we focus on how acetylation may control the degradation and turnover of mitochondria, the major source of fuel-derived acetyl-CoA.     

Reactions of the autonomic nervous system of students with different characteristics of higher nervous activity in the situation of examination stress

The influence of examination stress on the reactions of the autonomic nervous system in students with different levels of functional mobility of nervous processes (FMNP) was studied. More intense functioning of the cardiovascular system and the strain of all regulatory mechanisms during examination stress were characteristic of individuals with low FMNP, whereas students with high FMNP values were characterized by a weaker strain of the mechanisms of cardiac rhythm regulation, more economical activity of the cardiovascular system, and better performance on the examinations. The activation of humoral, metabolic, and sympathetic effects was observed in all the subjects under examination stress, along with decreased parasympathetic effects on the cardiac rhythm.     

A time to fast,a time to feast: The crosstalk between metabolism and the circadian clock

The cyclic environmental conditions brought about by the 24 h rotation of the earth have allowed the evolution of endogenous circadian clocks that control the temporal alignment of behaviour and physiology, including the uptake and processing of nutrients. Both metabolic and circadian regulatory systems are built upon a complex feedback network connecting centres of the central nervous system and different peripheral tissues. Emerging evidence suggests that circadian clock function is closely linked to metabolic homeostasis and that rhythm disruption can contribute to the development of metabolic disease. At the same time, metabolic processes feed back into the circadian clock, affecting clock gene expression and timing of behaviour. In this review, we summarize the experimental evidence for this bimodal interaction, with a focus on the molecular mechanisms mediating this exchange, and outline the implications for clock-based and metabolic diseases.     

The logic of the hepatic methionine metabolic cycle

This review describes our current understanding of the “traffic lights” that regulate sulfur flow through the methionine bionetwork in liver, which supplies two major homeostatic systems governing cellular methylation and antioxidant potential. Theoretical concepts derived from mathematical modeling of this metabolic nexus provide insights into the properties of this system, some of which seem to be paradoxical at first glance. Cellular needs supported by this network are met by use of parallel metabolic tracks that are differentially controlled by intermediates in the pathway. A major task, i.e. providing cellular methylases with the methylating substrate, S-adenosylmethionine, is met by flux through the methionine adenosyltransferase I isoform. On the other hand, a second important function, i.e., stabilization of the blood methionine concentration in the face of high dietary intake of this amino acid, is achieved by switching to an alternative isoform, methionine adenosyltransferase III, and to glycine N-methyl transferase, which together bypass the first two reactions in the methionine cycle. This regulatory strategy leads to two metabolic modes that differ in metabolite concentrations and metabolic rates almost by an order of magnitude. Switching between these modes occurs in a narrow trigger zone of methionine concentration. Complementary experimental and theoretical analyses of hepatic methionine metabolism have been richly informative and have the potential to illuminate its response to oxidative challenge, to methionine restriction and lifespan extension studies and to diseases resulting from deficiencies at specific loci in this pathway.     

The Control of the Controller: Molecular Mechanisms for Robust Perfect Adaptation and Temperature Compensation

Organisms have the property to adapt to a changing environment and keep certain components within a cell regulated at the same level (homeostasis). “Perfect adaptation” describes an organism's response to an external stepwise perturbation by regulating some of its variables/components precisely to their original preperturbation values. Numerous examples of perfect adaptation/homeostasis have been found, as for example, in bacterial chemotaxis, photoreceptor responses, MAP kinase activities, or in metal-ion homeostasis. Two concepts have evolved to explain how perfect adaptation may be understood: In one approach (robust perfect adaptation), the adaptation is a network property, which is mostly, but not entirely, independent of rate constant values; in the other approach (nonrobust perfect adaptation), a fine-tuning of rate constant values is needed. Here we identify two classes of robust molecular homeostatic mechanisms, which compensate for environmental variations in a controlled variable's inflow or outflow fluxes, and allow for the presence of robust temperature compensation. These two classes of homeostatic mechanisms arise due to the fact that concentrations must have positive values. We show that the concept of integral control (or integral feedback), which leads to robust homeostasis, is associated with a control species that has to work under zero-order flux conditions and does not necessarily require the presence of a physico-chemical feedback structure. There are interesting links between the two identified classes of homeostatic mechanisms and molecular mechanisms found in mammalian iron and calcium homeostasis, indicating that homeostatic mechanisms may underlie similar molecular control structures.     

Quantitative assessment of regulation in metabolic systems

We show how metabolic regulation as commonly understood in biochemistry can be described in terms of metabolic control analysis. The steady-state values of the variables of metabolic systems (fluxes and concentrations) are determined by a set of parameters. Some of these parameters are concentrations that are set by the environment of the system; they can act as external regulators by communicating changes in the environment to the metabolic system. How effectively a system is regulated depends both on the degree to which the activity of the regulatory enzyme with which a regulator interacts directly can be altered by the regulator (its regulability) and on the ability of the regulatory enzyme to transmit the changes to the rest of the system (its regulatory capacity). The regulatory response of a system also depends on its internal organisation around key variable metabolites that act as internal regulators. The regulatory performance of the system can be judged in terms of how sensitivity the fluxes respond to the external stimulus and to what degree homeostasis in the concentrations of the internal regulators is maintained. We show how, on the level of both external and internal regulation, regulability can be quantified in terms of an elasticity coefficient and regulatory capacity in terms of a control coefficient. Metabolic regulation can therefore be described in terms of metabolic control analysis. The combined response relationship of control analysis relates regulability and regulatory capacity and allows quantification of the regulatory importance of the various interactions of regulators with enzymes in the system. On this basis we propose a quantitative terminology and analysis of metabolic regulation that shows what we should measure experimentally and how we should interpret the results. Analysis and numerical simulation of a simple model system serves to demonstrate our treatment.     

Maintaining the status quo: T-cell homeostasis

Lymphocyte numbers and subset composition are maintained at relatively constant levels throughout adulthood. Fluctuations in cell numbers due to infection, loss of cells, or other influences are smoothed out by unknown mechanisms that return the system to homeostasis. Regulation of lymphocyte numbers could be controlled at several points: rate of production, alteration in life span by diminution or enhancement of survival, or by division of cells within the compartment. Cell numbers within the immune system appear to be controlled by homeostatic mechanisms that influence each of these points. This discussion will focus on the regulation of peripheral cell numbers by the antigen-independent proliferation of T cells, which has recently been demonstrated to contribute to the maintenance and recovery of lymphocyte homeostasis.     

Phenotypic flexibility as key factor in the human nutrition and health relationship

Metabolic adaptation to a disturbance of homeostasis is determined by a series of interconnected physiological processes and molecular mechanisms that can be followed in space (i.e., different organs or organelles) and in time. The amplitudes of these responses of this “systems flexibility network” determine to what extent the individual can adequately react to external challenges of varying nature and thus determine the individual’s health status and disease predisposition. Connected pathways and regulatory networks act as “adaptive response systems” with metabolic and inflammatory processes as a core—but embedded into psycho-neuro-endocrine control mechanisms that in their totality define the phenotypic flexibility in an individual. Optimal metabolic health is thus the orchestration of all mechanisms and processes that maintain this flexibility in an organism as a phenotype. Consequently, onset of many chronic metabolic diseases results from impairment or even loss of flexibility in parts of the system. This also means that metabolic diseases need to be diagnosed and treated from a systems perspective referring to a “systems medicine” approach. This requires a far better understanding of the mechanisms involved in maintaining, optimizing and restoring phenotypic flexibility. Although a loss of flexibility in a specific part of the network may promote pathologies, this not necessarily takes place in the same part because the system compensates. Diagnosis at systems level therefore needs the quantification of the response reactions of all relevant parts of the phenotypic flexibility system. This can be achieved by disturbing the homeostatic system by any challenge from extended fasting, to intensive exercise or a caloric overload.     

Homeostatic mechanisms of biological systems: Development homeostasis

Homeostasis as an ability to maintain structural-functional parameters of the system at the required level is a basic characteristic for providing the stability of any biological system (from biosphere and separate ecosystems to communities, populations, and individuals). The study of homeostatic mechanisms that provide the stability of biological systems is the main task for solving many theoretical and practical questions. The search for criteria of homeostasis estimation and study of homeostatic mechanism ratio at different levels are principally important in this direction. Estimation of the role of homeostatic mechanisms of the organism and population for providing the stability of biological systems of different levels when using the approach based on estimation of the population state from ontogenetic positions (population developmental biology) seems promising.     

Leptin and metabolic control of reproduction

Leptin treatment prevents the effects of fasting on reproductive processes in a variety of species. The mechanisms that underlie these effects have not been elucidated. Progress in this area of research might be facilitated by viewing reproductive processes in relation to mechanisms that maintain fuel homeostasis. Reproduction, food intake, and fuel partitioning can be viewed as homeostatic responses controlled by a sensory system that monitors metabolic signals. These signals are generated by changes in intracellular metabolic fuel availability and oxidation rather than by changes in the amount of body fat or by changes in any aspect of body composition. Leptin might be viewed as either a mediator or as a modulator of the intracellular metabolic signal. Consistent with its purported action as a mediator of the metabolic signal, leptin synthesis and secretion are influenced acutely by changes in metabolic fuel availability, and these changes might lead to changes in reproductive function. The effects of leptin treatment on reproduction are blocked by treatments that inhibit intracellular fuel oxidation. Metabolic signals that inhibit reproduction in leptin-treated animals might act via neural pathways that are independent of leptin's action. Alternatively, both leptin and metabolic inhibitors might interact at the level of intracellular fuel oxidation. In keeping with the possibility that leptin modulates the metabolic signal, leptin treatment increases fuel availability, uptake, and oxidation in particular tissues. Leptin might affect reproduction indirectly by altering fuel oxidation or other peripheral processes such as gastric emptying. Reproductive processes are among the most energetically expensive in the female repertoire. Because leptin increases energy expenditure while simultaneously inhibiting energy intake, it may have limited use as a long-term treatment for infertility.     

Regulatory mechanisms that govern nicotinic synapse formation in neurons

Individual cholinoceptive neurons express high levels of different neuronal nicotinic acetylcholine receptor (nAChR) subtypes, and target them to the appropriate synaptic regions for proper function. This review focuses on the intercellular and intracellular processes that regulate nAChR expression in vertebrate peripheral nervous system (PNS) and central nervous system (CNS) neurons. Specifically, we discuss the cellular and molecular mechanisms that govern the induction and maintenance of nAChR expression-innervation, target tissue interactions, soluble factors, and activity. We define the regulatory principles of interneuronal nicotinic synapse differentiation that have emerged from these studies. We also discuss the molecular players that target nAChRs to the surface membrane and the interneuronal synapse.     

Principles of Physiological Regulation of the Body Functions in Incomplete Adaptation

The main condition of completing the process of adaptation of the body to the effect of an external factor is the return of the homeostatic system parameters to their initial levels or their stabilization at a new level. The article considers the state of incomplete adaptation (IA) based on the process of the stabilization of systemic reactions (respiration and blood circulation) on repeated exposure to extreme environmental factors (hypoxia and cold) associated with the excitation of the central regulatory mechanisms of the respiratory center system performing a compensatory–protective function. It is postulated that a change in the afferent information flows (the thresholds of excitation and reactivity of the peripheral receptor systems) forms the basis of IA. The IA state is supposed to persist for an indefinitely long period of time due to insufficient functional reserves and to be the cause of psychosomatic pathology.     

Histone acetylation facilitates association of nucleosomes with SET domain of ALL-1 methyltransferase in vitro

The inheritable methylation pattern of gene activity, created upon cell differentiation, is further maintained by the “SET” (methyltransferase)-domain proteins. However, it is still not clear how SET-proteins can decide on the required gene activity state and the way their chromatin association is maintained. Here we have found that high levels of histone acetylation - the hallmarks of active chromosome regions in vivo - can increase the affinity of reconstituted nucleosomes to the SET domain of ALL-1 histone methyltransferase in a defined system in vitro.     

Genetic engineering of carotenoid formation in tomato fruit and the potential application of systems and synthetic biology approaches

The health benefits conferred by numerous carotenoids have led to attempts to elevate their levels in foodstuffs. Tomato fruit and its products contain the potent antioxidant lycopene and are the predominant source of lycopene in the human diet. In addition, tomato products are an important source of provitamin A (β-carotene). The presence of other health promoting phytochemicals such as tocopherols and flavonoids in tomato has led to tomato and its products being termed a functional food. Over the past decade genetic/metabolic engineering of carotenoid biosynthesis and accumulation has resulted in the generation of transgenic varieties containing high lycopene and β-carotene contents. In achieving this important goal many fundamental lessons have been learnt. Most notably is the observation that the endogenous carotenoid pathways in higher plants appear to resist engineered changes. Typically, this resistance manifests itself through intrinsic regulatory mechanisms that are “silent” until manipulation of the pathway is initiated. These mechanisms may include feedback inhibition, forward feed, metabolite channelling, and counteractive metabolic and cellular perturbations. In the present article we will review progress made in the genetic engineering of carotenoids in tomato fruit, highlighting the limiting regulatory mechanisms that have been observed experimentally. The predictability and efficiency of the present engineering strategies will be questioned and the potential of more Systems and Synthetic Biology approaches to the enhancement of carotenoids will be assessed.     

Kinetic Mechanisms of Biological Regulation in Photosynthetic Organisms

Principles of regulation on different levels of photosynthetic apparatus are discussed. Mathematical models of isolated photosynthetic reaction centers and general system of energy transduction in chloroplast are developed. A general approach to model these complex metabolic systems is suggested. Regulatory mechanisms in plant cell are correlated with the different patterns of fluorescence induction curve at different internal physiological states of the cells and external (environmental) conditions. Light regulation inside photosynthetic reaction centers, diffusion processes in thylakoid membrane, generation of transmembrane electrochemical potential, coupling with processes of CO₂ fixation in Calvin Cycle are considered as stages of control of energy transformation in chloroplasts in their connection with kinetic patterns of fluorescence induction curves and other spectrophotometric data.     

Hormones and the levels of humoral regulation]

The problems on the place of hormones secreted by "classical" endocrine glands, on their relationship with other compounds that possess physiological activity, criteria that determine the definition "hormone" are considered in this article. The conception about the levels of the humoral regulatory systems that are organized and formed during phylogenesis and ontogenesis and provide a consecutive increase in their complexity and mobility of adaptation to changes of environment and internal conditions are substantiated on the basis of numerous data. The metabolites that are products of nonspecific activity of any cell of the multicellular organism form the first and simplest level of humoral regulatory organization. The next (second) level of humoral organization is also formed by chemically simple substances. However, these substances are specialized products of the secretory activity of cells and exert potent influence on the physiological processes. Neuroamines and regulatory peptides are applied to these agents, in the first place. They arise simultaneously and jointly at the first stage of ontogenesis. The distinctive characters of the third level of the humoral regulation are increased and complication of the regulatory activity conditioned by cooperative influences of humoral agents produced by single secretory elements situated outside the classical endocrine glands. The chemically and originally different substances causing predominantly local effects are attributed to these physiologically active substances. Their participation in general adaptive reactions as well as inclusion of classical hormones into hierarchy of humoral regulation signify the formation of the forth regulatory level that provides realization of general homeostatic reactions peculiar to the whole organism.(ABSTRACT TRUNCATED AT 250 WORDS)