O12 Implication de la Cx43 dans la détection hypothalamique du glucose

Introduction L'hypothalamus est fortement implique dans la regulation nerveuse de l'homeostasie glucidique. La detection de l'hyperglycemie par des neurones specialises declenche des reponses adaptees comme le maintien de la glycemie ou encore le rassasiement. Les astrocytes sont suspectes participer a la detection neuronale du glucose. Ils sont organises en reseaux et presentent un grand nombre de jonctions gap (JG) permettant le passage du glucose de la circulation sanguine vers les neurones. Ces JG sont formees majoritairement de connexine 43 (Cx43). Nous avons fait l'hypothese que les reseaux astrocytaires, via les Cx43 en particulier, participent a la detection hypothalamique du glucos…

Implication of Cx43 in hypothalamic detection of glucosis.

Meeting Abstract ; WOS: 000302819400014; International audience

PO39 La fission mitochondriale induite par le glucose est indispensable à la signalisation ROS lors de la détection hypothalamique de l’hyperglycémie

Introduction Nous avons montre que la detection hypothalamique de l’hyperglycemie (HG) fait intervenir une signalisation ROS d’origine mitochondriale, laquelle est indispensable aux reponses effectrices, dont la secretion d’insuline. Par ailleurs, des etudes recentes montrent que la morphologie des mitochondries varie lors de l’HG, morphologie qui est dependante de la dynamique mitochondriale, modifiant alors la production de ROS. Ainsi, l’inhibition de la fission mitochondriale diminue la production de ROS lors d’une hyperglycemie dans l’hepatocyte par exemple. Objectif Comprendre si, in vivo, la signalisation par les ROS lors du « glucose sensing » hypothalamique, implique la dynamique mi…

Implication de l’apéline hypothalamique dans la mise en place d’un diabète de type 2 par le contrôle de la production hépatique de glucose via le système nerveux autonome

Enhanced Hypothalamic Glucose Sensing in Obesity: Alteration of Redox Signalling

1939-327X (Electronic) Journal article; Objective : 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, modific…

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. RESEARCH DESIGN AND METHODS—ROS production in response to glucose was investigated in freshly isolated rat islets. ROS effects were studied using a pharmacological approach and calcium imaging. RESULTS—Transient glucose increase …

Evidence for hypothalamic ketone bodies sensing: impact on food intake and peripheral metabolic responses in mice

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain keton…

Détection cérébrale du glucose, plasticité neuronale et métabolisme énergétique

Resume L’apport d’energie est, dans la plupart des cas extremement, bien controle et est ajuste aux depenses d’energie d’un individu donne, c’est ce que l’on nomme l’homeostasie energetique. Cet equilibre repose en grande partie sur la capacite du systeme nerveux central a evaluer le statut energetique de l’organisme, en integrant differents signaux provenant de la peripherie dont le glucose. Cette revue porte sur les decouvertes recentes concernant l’identification des differents mecanismes cellulaires et moleculaires, des types cellulaires et de leur phenotype, des reseaux neuronaux et de leur plasticite. Ainsi il est maintenant etabli qu’il existe differents types de neurones repondant, …

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

Aims: We have previously demonstrated that central apelin is implicated in the control of peripheral glycemia, and its action depends on nutritional (fast versus fed) and physiological (normal versus diabetic) states. An intracerebroventricular (icv) injection of a high dose of apelin, similar to that observed in obese/diabetic mice, increase fasted glycemia, suggesting (i) that apelin contributes to the establishment of a diabetic state, and (ii) the existence of a hypothalamic to liver axis. Using pharmacological, genetic, and nutritional approaches, we aim at unraveling this system of regulation by identifying the hypothalamic molecular actors that trigger the apelin effect on liver gluc…

Hypothalamic Astroglial Connexins are Required for Brain Glucose Sensing-Induced Insulin Secretion

Supplementary Information accompanies the paper on the Journal of Cerebral Blood Flow & Metabolism website; Hypothalamic glucose detection participates in maintaining glycemic balance, food intake, and thermogenesis. Although hypothalamic neurons are the executive cells involved in these responses, there is increasing evidence that astrocytes participate in glucose sensing (GS); however, it is unknown whether astroglial networking is required for glucose sensitivity. Astroglial connexins 30 and 43 (Cx30 and Cx43) form hexameric channels, which are apposed in gap junctions, allowing for the intercellular transfer of small molecules such as glucose throughout the astroglial networks. Here, we…

Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats.

International audience; AIMS: Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing. RESULTS: Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expressio…

Détection hypothalamique de l’hyperglycémie : rôle de la dynamique mitochondriale dans la signalisation par les espèces actives de l’oxygène

Alteration of hypothalamic glucose and lactate sensing in 48h hyperglycemic rats.

International audience; Hypothalamic detection of nutrients is involved in the control of energy metabolism and is altered in metabolic disorders. Although hypothalamic detection of blood lactate lowers hepatic glucose production and food intake, it is unknown whether it also modulates insulin secretion. To address this, a lactate injection via the right carotid artery (cephalad) was performed in Wistar rats. This triggered a transient increase in insulin secretion. Rats made hyperglycemic for 48h exhibited prolonged insulin secretion in response to a glucose injection via the carotid artery, but lactate injection induced two types of responses: half of the HG rats showed no difference comp…

032 Implication de la Cx43 dans le glucose-sensing hypothalamique

Introduction L’hypothalamus est fortement implique dans la regulation de l’homeostasie glucidique. Les variations de glycemie y sont detectees par des neurones specialises, notamment dans le noyau arque : on parle de « glucose-sensing » (GS). L’integration de cette information declenche une reponse adaptee afin de maintenir la glycemie stable. L’acheminement du glucose de la circulation aux neurones implique les astrocytes. Ces derniers forment un reseau via les jonctions gap (JG) qui permet le trafic de metabolites, dont le glucose, entre astrocytes et avec le milieu extracellulaire. Ces jonctions sont formees majoritairement de connexines 43 (Cx43), hemi-canaux fortement exprimes dans l’h…

Hypothalamic S-Nitrosylation Contributes to the Counter-Regulatory Response Impairment following Recurrent Hypoglycemia

http://www.ncbi.nlm.nih.gov/pubmed/23894333; International audience; AIMS: Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction b…

Hypothalamic glucose sensing : mitochondrial dynamic involument in reactive oxygen species signaling

Energetic homeostasis results in the balance between energy intake and expenditure. The hypothalamus plays an important role in the regulation of both energetic metabolism and food intake in sensing hormonal and metabolic signals. For instance, changes in hypothalamic glucose level modulate food intake and insulin secretion. We have previously found that 1) increased hypothalamic glucose level triggers production of mitochondrial reactive oxygen species (mROS) from the electron transport chain; 2) hypothalamic mROS production is involved in glucose homeostasis and food intake control. The molecular mechanisms involved in glucose-induced hypothalamic mROS production are still unknown. Mitoch…

Method for functional study of mitochondria in rat hypothalamus

1872-678X (Electronic) Journal Article Research Support, Non-U.S. Gov't; Different roles of mitochondria in brain function according to brain area are now clearly emerging. Unfortunately, no technique is yet described to investigate mitochondria function in specific brain area. In this article, we provide a complete description of a procedure to analyze the mitochondrial function in rat brain biopsies. Our two-step method consists in a saponin permeabilization of fresh brain tissues in combination with high-resolution respirometry to acquire the integrated respiratory rate of the biopsy. In the first part, we carefully checked the mitochondria integrity after permeabilization, defined exper…

Glucose and hypothalamic astrocytes: More than a fueling role?

Brain plays a central role in energy homeostasis continuously integrating numerous peripheral signals such as circulating nutrients, and in particular blood glucose level, a variable that must be highly regulated. Then, the brain orchestrates adaptive responses to modulate food intake and peripheral organs activity in order to achieve the fine tuning of glycemia. More than fifty years ago, the presence of glucose-sensitive neurons was discovered in the hypothalamus, but what makes them specific and identifiable still remains disconnected from their electrophysiological signature. On the other hand, astrocytes represent the major class of macroglial cells and are now recognized to support an…

Glucose-induced mitochondrial fission through DRP1 is required for redox signaling in hypothalamic glucose sensing mechanism

Communication affichée; We previously showed that hypothalamic glucose sensing requires a redox signaling in hypothalamic arcuate nucleus, through glucose‐induced mitochondrial H2O2 production (1). ROS implication in nutrient sensing has been confirmed by others studies (2). Recent studies highlight mitochondrial morphology changes under glycemia increase, which depends on mitochondrial dynamics. Changes in mitochondrial dynamics are causative events in mitochondrial reactive oxygen species (mROS) production when glycemia rises. It has been demonstrates that mitochondrial fission blockade decreases mROS production during hyperglycemia in metabolic‐sensitive cells, such as hepatocytes or myo…