Recurrent Hypoglycemia Is Associated with Loss of Activation in Rat Brain Cingulate Cortex

A subset of people with diabetes fail to mount defensive counterregulatory responses (CRR) to hypoglycemia. Although the mechanisms by which this occurs remain unclear, recurrent exposure to hypoglycemia may be an important etiological factor. We hypothesized that loss of CRR to recurrent exposure to hypoglycemia represents a type of stress desensitization, in which limbic brain circuitry involved in modulating stress responses might be implicated. Here, we compared activation of limbic brain regions associated with stress desensitization during acute hypoglycemia (AH) and recurrent hypoglycemia (RH). Healthy Sprague Dawley rats were exposed to either acute or recurrent 3-d hypoglycemia. We also examined whether changes in neuronal activation were caused directly by the CRR itself by infusing epinephrine, glucagon, and corticosterone without hypoglycemia. AH increased neuronal activity as quantified by c-fos immunoreactivity (FOS-IR) in the cingulate cortex and associated ectorhinal and perirhinal cortices but not in an adjacent control area (primary somatosensory cortex). FOS-IR was not observed after hormone infusion, suggesting that AH-associated activation was caused by hypoglycemia rather than by CRR. Importantly, AH FOS-IR activation was significantly blunted in rats exposed to RH. In conclusion, analogous with other models of stress habituation, activation in the cingulate cortex and associated brain areas is lost with exposure to RH. Our data support the hypothesis that limbic brain areas may be associated with the loss of CRR to RH in diabetes

Role of Central Nervous System Glucagon-Like Peptide-1 Receptors in Enteric Glucose Sensing

OBJECTIVE—Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system

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

CNS targets of adipokines

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.Our understanding of adipose tissue as an endocrine organ has been transformed over the last twenty years. During this time a number of adipocyte-derived factors or adipokines have been identified. This paper will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be the focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted

Sensibilité au glucose du cerveau chez le rat (implication de l'hypothalamus, détermination des acteurs cellulaires et moléculaires)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: involvement of astrocytes in cerebral glucose-sensing in rats

International audienc

Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: involvement of astrocytes in cerebral glucose-sensing in rats

International audienc

Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons

1479-6805 (Electronic) Journal ArticleAdiponectin is involved in the control of energy homeostasis in peripheral tissues through Adipor1 and Adipor2 receptors. An increasing amount of evidence suggests that this adipocyte-secreted hormone may also act at the hypothalamic level to control energy homeostasis. In the present study, we observed the gene and protein expressions of Adipor1 and Adipor2 in rat hypothalamus using different approaches. By immunohistochemistry, Adipor1 expression was ubiquitous in the rat brain. By contrast, Adipor2 expression was more limited to specific brain areas such as hypothalamus, cortex, and hippocampus. In arcuate and paraventricular hypothalamic nuclei, Adipor1, and Adipor2 were expressed by neurons and astrocytes. Furthermore, using transgenic green fluorescent protein mice, we showed that Adipor1 and Adipor2 were present in pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) neurons in the arcuate nucleus. Finally, adiponectin treatment by intracerebroventricular injection induced AMP-activated protein kinase (AMPK) phosphorylation in the rat hypothalamus. This was confirmed by in vitro studies using hypothalamic membrane fractions. In conclusion, Adipor1 and Adipor2 are both expressed by neurons (including POMC and NPY neurons) and astrocytes in the rat hypothalamic nuclei. Adiponectin is able to increase AMPK phosphorylation in the rat hypothalamus. These data reinforced a potential role of adiponectin and its hypothalamic receptors in the control of energy homeostasis