Fourth ventricular alloxan injection causes feeding but not hyperglycemia in rats

Ritter, Sue; Strang, Mary

doi:10.1016/0006-8993(82)90190-1

Cited by 34 publications

(19 citation statements)

References 16 publications

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“…2A). These results are consistent with a previous study [22] showing that 20 µg alloxan injection into the 4V did not alter blood glucose levels. Taken together, these findings suggest that glucose-sensing cells involved in glucoprivic suppression of pulsatile LH secretion and the acute feeding response to glucoprivation may be different from those responsible for glucose homeostasis.…”

Section: Discussionsupporting

confidence: 93%

“…The same group reported that 20 µg of alloxan injected acutely into the 4V induced feeding behavior but did not change the glucoprivic feeding response in rats [22]. Thus, alloxan injection at the dose of 20 µg in the present study probably did not cause any permanent damage to the putative glucose-sensing cells in the 4V, but acutely inhibited GK activity in those cells, thereby mimicking a hypoglycemic condition.…”

Section: Discussionsupporting

confidence: 41%

“…The doses were chosen because a previous study reported that 15 or 20 µg but not 10 µg of alloxan increased food intake [22]. In addition, the administration of 40 µg of alloxan into the lateral cerebral ventricle [17] impairs glucoprivic feeding, but 20 µg of alloxan did not [22].…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Fourth Ventricular Alloxan Injection Suppresses Pulsatile Luteinizing Hormone Release in Female Rats

Kinoshita

I’Anson

Tsukamura

et al. 2004

Journal of Reproduction and Development

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Abstract. Previous studies have suggested the presence of a glucose-sensing mechanism in the hindbrain that appears to regulate reproductive function as well as feeding behavior. The ependymocytes lining the ventricular wall of the hindbrain showed immunoreactivities to pancreatic glucokinase (GK), a key enzyme for glucose sensing in pancreatic B cells. Our goal in the present study was to test whether the GK-immunopositive ependymocytes in the wall of the fourth cerebroventricle (4V) play a role in regulating gonadal activity. Our approach was to determine the effect of injecting alloxan, a GK inhibitor, into the 4V on pulsatile luteinizing hormone (LH) secretion.Estrogen-primed ovariectomized rats received an injection of alloxan (10 or 20 µg/animal) into the 4V and blood samples were collected every 6 min for 3 h for measurement of blood LH, corticosterone and glucose levels. Pulsatile LH secretion was suppressed after alloxan injection and all pulse parameters were significantly (P<0.05) inhibited by 20 µg alloxan. Plasma corticosterone levels were increased significantly (P<0.05) by 20 µg alloxan, suggesting that LH pulse suppression by alloxan may be at least partly mediated by activation of the hypothalamo-pituitary-adrenal axis. The present results suggest that acute suppression of GK activity in the hindbrain inhibits pulsatile LH secretion in female rats, and supports the idea that GK-immunopositive ependymocytes may sense glucose levels in the cerebrospinal fluid and play a role in regulation of LH secretion. Key words: Alloxan, LH, Glucokinase, Hindbrain, Ependymocytes (J. Reprod. Dev. 50: [279][280][281][282][283][284][285] 2004) t has been well established that reduction of glucose availability inhibits the activity of the hypothalamo-pituitary-gonadal axis in mammalian species [1][2][3]. Pharmacological glucoprivation induced by systemic injection of a glucose antagonist, 2-deoxy-D-glucose (2DG), inhibits estrous cyclicity in female hamsters [1] and rats [4], and pulsatile luteinizing hormone (LH) release in female rats [5]. Glucose availability might monitored by a glucose-sensing mechanism either in the peripheral organs and/or brain to regulate gonadotropin secretion and then reproductive functions.It is now well accepted that glucose-sensing regions are at least partly located in the brain. In addition to several hypothalamic areas, such as the hypothalamic ventromedial, paraventricular and arcuate nuclei and lateral hypothalamic area [6][7][8], the hindbrain has also been suggested as a glucosesensing region, because food intake is increased by 5-thio-D-glucose (5TG) infusion into the fourth cerebroventricle (4V) but not into the third cerebroventricle (3V) in rats with an obstruction of the connection between the 3V and 4V [9]. Feeding is also induced by local application of 5TG into the

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 41%

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Fourth Ventricular Alloxan Injection Suppresses Pulsatile Luteinizing Hormone Release in Female Rats

Kinoshita

I’Anson

Tsukamura

et al. 2004

Journal of Reproduction and Development

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“…65,66 For instance, pharmacological inhibition of glucokinase by intracerebroventricular alloxan injections induced feeding. 92 Thus, as for counter-regulation, the control of feeding by glucose appears to depend on glucose sensing by several sites, which may also be present in the hepatoportal vein region, the brainstem and the hypothalamus. These different sites clearly interact with each other and the control of feeding in physiological conditions may rely mostly on portal and brainstem glucose sensing, signals that are then integrated at the melanocortin pathway.…”

Section: Feeding Controlmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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“…To do this, we used alloxan, which pharmacologically inhibits GK activity at low doses (19,20), but induces cell death at higher concentrations, presumably through the production of reactive oxygen radicals (21,22). Previous studies have reported that pharmacological concentrations of alloxan delivered centrally stimulate feeding, but not sympathoadrenal activation (23). Conversely, toxic concentrations permanently abolish the feeding, but not the sympathoadrenal response to glucoprivation (24 -27).…”

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confidence: 99%

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

2004

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Glucokinase (GK) is hypothesized to be the critical glucosensor of pancreatic ␤-cells and hypothalamic glucosensing neurons. To understand the role of GK in glucoprivic counterregulatory responses, we injected alloxan, a GK inhibitor and toxin, into the third ventricle (3v) to target nearby GK-expressing neurons. Four and 6 days after 3v, but not 4v, alloxan injection, alloxan-treated rats ate only 30% and their blood glucose area under the curve was only 28% of saline controls' after systemic 2-deoxy-D-glucose. In addition, their hyperglycemic response to hindbrain glucoprivation induced with 5-thio-glucose was impaired, whereas fasting blood glucose levels and food intake after an overnight fast were elevated. These impaired responses were associated with the destruction of 3v tanycytes, reduced glial fibrillary acidic protein-immunoreactivity surrounding the 3v, neuronal swelling, and decreased arcuate nucleus neuropeptide Y (NPY) mRNA. Nevertheless, hypothalamic GK mRNA was significantly elevated. Two weeks after alloxan injection, 3v tanycyte destruction was reversed along with restoration of feeding and hyperglycemic responses to both systemic and hindbrain glucoprivation. At this time there were significant decreases in GK, NPY, and proopiomelanocortin mRNA. Thus, neural substrates near and around the 3v affected by alloxan may be critically involved in the expression of these glucoprivic responses. Diabetes 53: 1230 -1236, 2004 T he brain relies on a continuous supply of glucose as a primary energy source (1) and has evolved mechanisms that detect decreases in blood glucose levels and elicit autonomic, neuroendocrine, and behavioral counterregulatory responses (CRRs) that prevent and correct glucoprivation. One way in which the brain senses alterations in glucose availability is through specialized glucosensing neurons (2-6). These neurons utilize glucose as a signaling molecule to alter their membrane potential and firing rate, whereas the majority of neurons utilize glucose primarily to fuel their metabolic needs (2,3). As extracellular glucose levels decline, glucose-excited neurons decrease and glucoseinhibited neurons increase their action potential frequency (4,7-11). As is the case with pancreatic ␤-cells, it is hypothesized that the high-K m glycolytic enzyme, glucokinase (GK), is a regulator of neuronal glucosensing within the physiological range (10,(12)(13)(14). GK inhibitors alter calcium flux (10,14) and neuronal firing (12) in ventromedial hypothalamus (VMH) glucosensing neurons, and GK mRNA is expressed in glucosensing neurons in the hypothalamic paraventricular nucleus (PVN), dorsomedial nucleus (DMN), ventromedial nucleus (VMN), and arcuate nucleus (ARC) (15,16). Specifically, GK is coexpressed in both ARC neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons (10). GK immunoreactivity (ir) is also localized in the ependymocytes lining the ventricles (17) and serotonin neurons in the midline medulla (17), where glucoprivic stimuli elicit CRRs (18).In vitro studies suggest that GK...

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Fourth ventricular alloxan injection causes feeding but not hyperglycemia in rats

Cited by 34 publications

References 16 publications

Fourth Ventricular Alloxan Injection Suppresses Pulsatile Luteinizing Hormone Release in Female Rats

Fourth Ventricular Alloxan Injection Suppresses Pulsatile Luteinizing Hormone Release in Female Rats

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

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