Neuropeptide Y in the arcuate nucleus is modulated by alterations in glucose utilization

Akabayashi, Akira; Zaia, Cássia Thaïs Bussamra Vieira; Silva, Iván; Chae, Hee Jin; Leibowitz, Sarah F.

doi:10.1016/0006-8993(93)90125-7

Cited by 83 publications

(33 citation statements)

References 44 publications

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“…Although NPY mRNA expression was reduced 4 days postalloxan injection when CRRs were impaired, both NPY and POMC expression was decreased at 14 days when glucoprivic responses returned to normal. However, impaired NPY signaling may be important for glucoprivic responses under some conditions, since glucoprivic feeding increases ARC NPY mRNA expression (47,48) and NPY antibodies block glucoprivic feeding (49). Finally, the earlier reduction in NPY expression is likely due to the fact that NPY neurons lie close to the tanycytes lining the 3v and would have been damaged before the more laterally placed POMC neurons by alloxan diffusing from the 3v.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

2004

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“…As described above, this involves an increase in NPY and CORT activity at the onset of the natural feeding cycle, to assist in replenishing these stores, and it is followed by a decline in this peptide and steroid during the first 2-3 h after the initiation of feeding (166). Thus, a disturbance in glucose utilization, also manifested under conditions of food deprivation and exercise, appears to be a critical signal for the stimulation of NPY production (231). States of obesity, diabetes and hypercortisolemia, are also associated with abnormal glucose homeostasis, and, consequently, increased NPY (208,231).…”

Section: Adrenal Steroids and Their Receptors In Relation To Normal Bmentioning

confidence: 96%

“…This signal, which develops during periods of little eating, presumably indicates a decline in glucose uptake or utilization. With peripheral injections of 2-deoxy-D-glucose (2-DG), Akabayashi et al (231) have provided evidence showing inhibition of glucose utilization to stimulate the release of CORT and subsequently enhance NPY synthesis in the ARC. A similar response can also be detected after central administration of dibutyryl CAMP, which together with the 2-DG results may reflect the normal, inverse relation between endogenous CAMP and cellular glucose utilization (232).…”

Section: Interactions Between Cort Insulin and Hypothalamic Neurochementioning

confidence: 99%

“…Thus, a disturbance in glucose utilization, also manifested under conditions of food deprivation and exercise, appears to be a critical signal for the stimulation of NPY production (231). States of obesity, diabetes and hypercortisolemia, are also associated with abnormal glucose homeostasis, and, consequently, increased NPY (208,231). What remains to be demonstrated is that this increase in NPY, a marker of disturbed glucose homeostasis, actually contributes in a significant fashion to the associated hyperphagia, lipogenesis and body weight gain (203,(262)(263)(264)(271)(272)(273)(274)).…”

Section: Adrenal Steroids and Their Receptors In Relation To Normal Bmentioning

confidence: 99%

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Adrenal Steroid Receptors: Interactions with Brain Neuropeptide Systems in Relation to Nutrient Intake and Metabolism

Tempel

Leibowitz

1994

J Neuroendocrinology

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195

127

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The glucocorticoid, corticosterone (CORT), is believed to have an important function in modulating nutrient ingestion and metabolism. Recent evidence described in this review suggests that the effects of this adrenal hormone are mediated through two steroid receptor subtypes, the type I mineralocorticoid receptor and the type II glucocorticoid receptor. These receptors, which have different affinities for CORT, respond to different levels of circulating hormone. They mediate distinct effects of the steroid, which can be distinguished by the specific nutrient ingested and by the particular period of the circadian cycle.Under normal physiological conditions, the type I receptor is tonically activated, either by low basal levels of circulating CORT (0.5-2 pg%) normally available across the circadian cycle or possibly by the mineralocorticoid aldosterone. This type I activation is required for the maintenance of fat ingestion and fat deposition that occurs during most meals of the feeding cycle. In contrast, the type II receptor is phasically activated by moderate levels of CORT (2-1 0 pg%) normally reached during the circadian peak. Activation of this receptor is required for the natural surge in carbohydrate ingestion and metabolism that is essential at the onset of the active feeding cycle when the body's glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. This receptor is also activated during periods of increased energy requirements, such as, after exercise and food restriction, when CORT levels rise further ( > 10 pg%) and when its catabolic effects on fat and protein stores predominate to provide additional substrates for glucose homeostasis. These functions of CORT on fat and carbohydrate balance are mediated, in part, by type I and type II receptors located within the hypothalamic paraventricular nucleus, which is known to have key functions in controlling nutrient intake and metabolism, as well as circulating CORT levels. Moreover, the type II receptors within this nucleus, in addition to the arcuate nucleus, may interact positively with the peptide, neuropeptide Y, and the catecholamine, norepinephrine, both of which act to enhance natural carbohydrate feeding and CORT release at the onset of the natural feeding cycle.Thus, under normal conditions, endogenous CORT has a primary function in controlling nutrient ingestion and metabolism over the natural circadian cycle, through the coordinated action of the type I and type II steroid receptor systems. Through this action, CORT has impact on total caloric intake and body weight gain over the long term. Moreover, under conditions of obesity, diabetes and food restriction, steroid receptor function is greatly disturbed in association with chronic high circulating levels of CORT and abnormal glucose homeostasis. These disturbances in steroid action, along with dysfunction in brain neurochemical processes, very possibly contribute to the maintenance of hyperphagia and body weight gain in obese and diabetic ...

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“…Induction of intracellular glucopenia with the glucose antimetabolite 2-deoxyglucose produces either no change (38,39) or an increase (40) in ARC NPY and no change in ARC POMC (38) mRNA or peptide levels. It is likely that increased ARC NPY expression in such circumstances is due to reduced energy availability.…”

Section: Hypoglycemia and Arcuate Nucleus Apoptosismentioning

confidence: 99%

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

2000

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Hypoglycemia reduces sympathoadrenal responses to subsequent hypoglycemic bouts by an unknown mechanism. To assess whether such hypoglycemia-associated autonomic failure is due to actual brain damage, male Sprague-Dawley rats underwent 1-h bouts of insulininduced (5 U/kg i.v.) hypoglycemia (1.6-2.8 mmol/l) 1 or 3 times on alternate days. Rats remained alert and were rescued with intravenous glucose at 60-80 min. Plasma epinephrine and corticosterone responses were significantly reduced during the second and third bouts. Brains from these rats were processed by the terminal transferase-mediated deoxyuridine triphosphatebiotin nick end-labeling ( W ith the advent of intensive insulin therapy for type 1 diabetes, there has been an increasing incidence of hypoglycemic episodes (1). Some of these are severe, resulting in coma and subsequent permanent brain damage and/or death (2-5). Other less severe hypoglycemic episodes do not impair consciousness. Regardless of degree, hypoglycemia is associated with a robust counterregulatory response (CRR) (6-9). Low levels of plasma glucose are sensed by selective neurons in the brain (10-14) as well as by glucosensors in the hepatic portal vein (15). Signals from these sensors provoke activation of the sympathoadrenal system with preferential release of epinephrine. In addition, cortisol is released from the adrenal cortex and glucagon from the pancreatic ␣-cells (6-9,16). This response maximizes the mobilization of glucose in the body. In addition to this CRR, subjects develop an awareness of their hypoglycemic state (6,9). Both the CRR and the hypoglycemia awareness can become blunted after only a single bout of hypoglycemia (9,17). Hypoglycemia awareness recovers fairly rapidly but the diminished CRR is often prolonged (6), suggesting that different mechanisms are responsible for the two phenomena. However, the mechanism underlying either of these remains unclear.Here, we present a rat model of the dampened CRR and show that a single bout of moderate hypoglycemia produces highly site-specific apparent apoptotic response in cells of the hypothalamic arcuate nucleus (ARC). This apoptosis is associated with a significant reduction in the expression of both neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA in this same nucleus. RESEARCH DESIGN AND METHODSAnimals and hypoglycemia. Male Sprague-Dawley rats were used at 300-400 g. They were housed at 22-23°C on a 12-h light-dark schedule and fed Purina rat chow (#5001) (PMI Nutrition International, Brentwood, MO) ad libitum. One group of rats (n = 12) had right atrial silastic catheters implanted via the right jugular vein under ketamine (45 mg/kg)/xylazine (9 mg/kg i.p.) anesthesia with buprenorphine (0.2 mg/kg) analgesia. Catheters were filled with a polyvinylpyrrolidone/heparin mix, which was replaced daily. The rats were allowed 4-5 days to recover and then were fasted overnight. Additional rats without venous catheters were also used (n = 34) and fasted overnight before testing. Between 0800 and 1000, a blood sample (...

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Neuropeptide Y in the arcuate nucleus is modulated by alterations in glucose utilization

Cited by 83 publications

References 44 publications

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

Adrenal Steroid Receptors: Interactions with Brain Neuropeptide Systems in Relation to Nutrient Intake and Metabolism

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

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