The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

The 5f localization/delocalization in square and hexagonal americium monolayers: A FP-LAPW electronic structure study

The electronic and geometrical properties of bulk americium and square and hexagonal americium monolayers have been studied with the full-potential linearized augmented plane wave (FP-LAPW) method. The effects of several common approximations are examined: (1) non-spin polarization (NSP) vs. spin polarization (SP); (2) scalar-relativity (no spin-orbit coupling (NSO)) vs. full-relativity (i.e., with spin-orbit (SO) coupling included); (3) local-density approximation (LDA) vs. generalized-gradient approximation (GGA). Our results indicate that both spin polarization and spin orbit coupling play important roles in determining the geometrical and electronic properties of americium bulk and monolayers. A compression of both americium square and hexagonal monolayers compared to the americium bulk is also observed. In general, the LDA is found to underestimate the equilibrium lattice constant and give a larger total energy compared to the GGA calculations. While spin orbit coupling shows a similar effect on both square and hexagonal monolayer calculations regardless of the model, GGA versus LDA, an unusual spin polarization effect on both square and hexagonal monolayers is found in the LDA results as compared with the GGA results. The 5f delocalization transition of americium is employed to explain our observed unusual spin polarization effect. In addition, our results at the LDA level of theory indicate a possible 5f delocalization could happen in the americium surface within the same Am II (fcc crystal structure) phase, unlike the usually reported americium 5f delocalization which is associated with crystal structure change. The similarities and dissimilarities between the properties of an Am monolayer and a Pu monolayer are discussed in detail.Comment: 22 pages, 8 figure

Possible common central pathway for resistin and insulin in regulating food intake.

Aim: Adipose tissue has been the object of intense research in the field of obesity and diabetes diseases in the last decade. Examination of adipocyte-secreted peptides led to the identification of a unique polypeptide, resistin (RSTN), which has been suggested as a link between obesity and diabetes. RSTN plays a clearly documented role in blocking insulin (INS)-induced hypoglycaemia. As brain injection of INS affects feeding behaviour, we studied the possible interaction between INS and RSTN in food-deprived rats, measuring effects on food intake. In addition, we examined how RSTN might affect neuropeptide Y (NPY)-induced feeding, as studies have shown that rat RSTN can interfere with the NPY system. Methods: Overnight food-deprived rats were injected into the third brain ventricle (3V) with either INS (10 or 20 mUI), RSTN (0.1–0.4 nmol/rat), or saline before access to food. Another group of rats was injected into the 3V with RSTN alone, NPY alone or RSTN plus NPY. Their food intake and body weight were measured. Results: Our results confirm the hypophagic effect of RSTN on food deprivation-induced food intake, and more importantly, show that RSTN neither potentiates nor blocks the effects of INS on food intake, but does reduce the hyperphagic effect of NPY. Conclusion:  The observation that RSTN does not modify feeding INS-induced hypophagia, but does influence NPY-induced feeding, points to the possibility that RSTN may be involved in control of food intake through an NPY-ergic mechanism as INS

Enhanced Hypothalamic Glucose Sensing in Obesity: Alteration of Redox Signaling

1939-327X (Electronic) Journal articleObjective : Recent data demonstrate that glucose sensing in different tissues is initiated by an intracellular redox-signaling pathway in physiological conditions. However, the relevance of such a mechanism in metabolic disease is not known. The aim of the present study was to determine whether brain-glucose hypersensitivity present in obese Zucker rat is related to an alteration in redox signaling. Research design and Methods: Brain glucose sensing alteration was investigated in vivo through the evaluation of electrical activity in arcuate nucleus, changes in ROS levels, and hypothalamic glucose-induced insulin secretion. In basal conditions, modifications of redox state and mitochondrial function were assessed through oxidized glutathione, glutathione peroxidase, manganese superoxide dismutase, aconitase activities and mitochondrial respiration. Results : Hypothalamic hypersensitivity to glucose was characterized by enhanced electrical activity of the arcuate nucleus and increased insulin secretion at a low glucose concentration, which does not produce such an effect in normal rats. It was associated with 1) increased ROS levels in response to this low glucose load, 2) constitutive oxidized environment coupled with lower antioxidant enzyme activity at both the cellular and mitochondrial level, and 3) over-expression of several mitochondrial subunits of the respiratory chain coupled with a global dysfunction in mitochondrial activity. Moreover, pharmacological restoration of the glutathione hypothalamic redox state by reduced-glutathione infusion in the third ventricle fully reversed the cerebral hypersensitivity to glucose. Conclusions : Altogether, these data demonstrate that obese Zucker rats' impaired hypothalamic regulation in terms of glucose sensing is linked to an abnormal redox signaling, which originates from mitochondria dysfunction

Local Ferromagnetism in Microporous Carbon with the Structural Regularity of Zeolite Y

Magnetization M(H,T) measurements have been performed on microporous carbon (MC) with a three-dimensional nano-array structure corresponding to that of a zeolite Y supercage. The obtained results unambiguously demonstrate the occurrence of high-temperature ferromagnetism in MC, probably originating from a topological disorder associated with curved graphene sheets. The results provide evidence that the ferromagnetic behavior of MC is governed by isolated clusters in a broad temperature range, and suggest the occurrence of percolative-type transition with the temperature lowering. A comparative analysis of the results obtained on MC and related materials is given.Comment: To be published in Physical Review B (2003

Surprises in the Orbital Magnetic Moment and g-Factor of the Dynamic Jahn-Teller Ion C_{60}^-

We calculate the magnetic susceptibility and g-factor of the isolated C_{60}^- ion at zero temperature, with a proper treatment of the dynamical Jahn-Teller effect, and of the associated orbital angular momentum, Ham-reduced gyromagnetic ratio, and molecular spin-orbit coupling. A number of surprises emerge. First, the predicted molecular spin-orbit splitting is two orders of magnitude smaller than in the bare carbon atom, due to the large radius of curvature of the molecule. Second, this reduced spin-orbit splitting is comparable to Zeeman energies, for instance, in X-band EPR at 3.39KGauss, and a field dependence of the g-factor is predicted. Third, the orbital gyromagnetic factor is strongly reduced by vibron coupling, and so therefore are the effective weak-field g-factors of all low-lying states. In particular, the ground-state doublet of C_{60}^- is predicted to show a negative g-factor of \sim -0.1.Comment: 19 pages RevTex, 2 postscript figures include

Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion

OBJECTIVE—Insulin secretion involves complex events in which the mitochondria play a pivotal role in the generation of signals that couple glucose detection to insulin secretion. Studies on the mitochondrial generation of reactive oxygen species (ROS) generally focus on chronic nutrient exposure. Here, we investigate whether transient mitochondrial ROS production linked to glucose-induced increased respiration might act as a signal for monitoring insulin secretion

A density functional study of molecular oxygen adsorption and reaction barrier on Pu (100) surface

Oxygen molecule adsorptions on a Pu (100) surface have been studied in detail, using the generalized gradient approximation to density functional theory. Dissociative adsorption with a layer by layer alternate spin arrangement of the plutonium layer is found to be energetically more favorable compared to molecular adsorption. Hor2 approach on a bridge site without spin polarization was found to the highest chemisorbed site with energy of 8.787 eV among all the cases studied. The second highest chemisorption energy of 8.236 eV, is the spin-polarized Hor2 or Ver approach at center site. Inclusion of spin polarization affects the chemisorption processes significantly, non-spin-polarized chemisorption energies being typically higher than the spin-polarized energies. We also find that the 5f electrons to be more localized in spin-polarized cases compared to the non-spin-polarized counterparts. The ionic part of O-Pu bonding plays a significant role, while the Pu 5f-O 2p hybridization was found to be rather week. Also, adsorptions of oxygen push the top of 5f band deeper away from the Fermi level, indicating further bonding by the 5f orbitals might be less probable. Except for the interstitial sites, the work functions increase due to adsorptions of oxygen

A global scientific strategy to cure hepatitis B

Chronic hepatitis B virus (HBV) infection is a global public health challenge on the same scale as tuberculosis, HIV, and malaria. The International Coalition to Eliminate HBV (ICE-HBV) is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, we have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure. We believe that research must focus on the discovery of interventional strategies that will permanently reduce the number of productively infected cells or permanently silence the covalently closed circular DNA in those cells, and that will stimulate HBV-specific host immune responses which mimic spontaneous resolution of HBV infection. There is also a pressing need for the establishment of repositories of standardised HBV reagents and protocols that can be accessed by all HBV researchers throughout the world. The HBV cure research agenda outlined in this position paper will contribute markedly to the goal of eliminating HBV infection worldwide

Hypothalamic Reactive Oxygen Species Are Required for Insulin-Induced Food Intake Inhibition: An NADPH Oxidase–Dependent Mechanism

1939-327X (Electronic) Journal Article Research Support, Non-U.S. Gov'tOBJECTIVE: Insulin plays an important role in the hypothalamic control of energy balance, especially by reducing food intake. Emerging data point to a pivotal role of reactive oxygen species (ROS) in energy homeostasis regulation, but their involvement in the anorexigenic effect of insulin is unknown. Furthermore, ROS signal derived from NADPH oxidase activation is required for physiological insulin effects in peripheral cells. In this study, we investigated the involvement of hypothalamic ROS and NADPH oxidase in the feeding behavior regulation by insulin. RESEARCH DESIGN AND METHODS: We first measured hypothalamic ROS levels and food intake after acute intracerebroventricular injection of insulin. Second, effect of pretreatment with a ROS scavenger or an NADPH oxidase inhibitor was evaluated. Third, we examined the consequences of two nutritional conditions of central insulin unresponsiveness (fasting or short-term high-fat diet) on the ability of insulin to modify ROS level and food intake. RESULTS: In normal chow-fed mice, insulin inhibited food intake. At the same dose, insulin rapidly and transiently increased hypothalamic ROS levels by 36%. The pharmacological suppression of this insulin-stimulated ROS elevation, either by antioxidant or by an NADPH oxidase inhibitor, abolished the anorexigenic effect of insulin. Finally, in fasted and short-term high-fat diet-fed mice, insulin did not promote elevation of ROS level and food intake inhibition, likely because of an increase in hypothalamic diet-induced antioxidant defense systems. CONCLUSIONS: A hypothalamic ROS increase through NADPH oxidase is required for the anorexigenic effect of insulin