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

O2 sensing by recombinant TWIK-related halothane-inhibitable K+ channel-1 background K+ channels heterologously expressed in human embryonic kidney cells

Hypoxic inhibition of K+ channels provides a link between low O2 and cell function, and in glossopharyngeal neurons hypoxic inhibition of a TWIK-related halothane-inhibitable K+ channel-1 (THIK-1)-like background K+ channel regulates neuronal function. In the present study, we examined directly the O2 sensitivity of recombinant THIK-1 channels, expressed in human embryonic kidney (HE293) cells. THIK-1 expression conferred a moderately outwardly rectifying halothane-inhibited and arachidonic acid-potentiated K+ current and invoked a strongly hyperpolarized resting membrane potential. Endogenous K+ currents in untransfected cells were unaffected by either agent. Hypoxia (P(O2), 20 mmHg) reversibly inhibited THIK-1 currents and caused membrane depolarization, effects that were occluded by halothane. Neither the mitochondrial complex I inhibitors rotenone, myxothiazol and sodium cyanide, nor the NADPH oxidase inhibitors diphenylene iodonium and phenylarsine oxide, were effective in inhibiting the O2-sensitivity of THIK-1. Thus, hypoxic inhibition of THIK-1 occurs by a mechanism dissimilar to that which regulates the activity of other members of the background K+ channel family. Given the O2 sensitivity of THIK-1 channels and their abundant expression in the CNS, we raise for the first time the possibility of a physiological and/or pathological role for these channels during brain ischemia

Process improvement in facilities management: The SPICE approach

Considers the application of structured process improvement for construction environments (SPICE) as a process improvement technique and its extension into the context of facilities management (FM). SPICE is a research project that developed a step-wise process improvement framework for the construction environment, utilising experience from the software industry, and in particular the capability maturity model (CMM), which has resulted in significant productivity improvements. Introduces the SPICE concept, a conceptual framework assessing the construction process capability. Commences by reviewing processes and their FM applicability and work on process improvement assessment in construction environments using the SPICE framework. Then discusses generalised principles of SPICE for process assessment. Considers its application and extension into the context of FM. Examines the specific example of FM process improvement and finally its implications. Furthermore, examines the relevance and accuracy of the framework, as well as its value to the FM organisation

Sorcin modulates cardiac L-type Ca²⁺ current by functional interaction with the alpha(1C) subunit in rabbits

We examined the modulation of the cardiac L-type Ca<sup>2+</sup> channel (LTCC) by the regulatory protein sorcin and tested the hypothesis that modulation occurred by direct interaction. Whole-cell patch-clamp recordings were made on native rabbit ventricular myocytes and HEK 293 cells expressing cardiac alpha(1C) subunits. In ventricular cells, sorcin increased peak current when using either Ca<sup>2+</sup> or Ba<sup>2+</sup> as charge carriers. In HEK 293 cells, sorcin increased peak current density when using Ba<sup>2+</sup> as a charge carrier but not when using Ca<sup>2+</sup>. In ventricular myocytes, current inactivation (tau(fast), in ms) was slowed by sorcin with Ca<sup>2+</sup> as the charge carrier, whilst in the presence of Ba2+ it was enhanced. In HEK 293 cells, sorcin significantly enhanced tau(fast), but no significant change was observed with Ba<sup>2+</sup>. This trend was mimicked by the truncated peptide, sorcin Ca<sup>2+</sup>-binding domain, which lacks the N-terminal domain. These data suggest that sorcin interacts with LTCC via its C-terminal domain, which alters current magnitude and tau(fast). These effects appear to be influenced by the prevailing experimental condition