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B E Levin

Publications and source records attributed to B E Levin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Localization of glucokinase gene expression in the rat brain.

The brain contains a subpopulation of glucosensing neurons that alter their firing rate in response to elevated glucose concentrations. In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production. A similar role for GK is proposed to underlie neuronal glucosensing. Via in situ hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large populations of glucosensing neurons (the arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the lateral area). GK also was found in brain areas without known glucosensing neurons (the lateral habenula, the bed nucleus stria terminalis, the inferior olive, the retrochiasmatic and medial preoptic areas, and the thalamic posterior paraventricular, interpeduncular, oculomotor, and anterior olfactory nuclei). Conversely, GK message was not found in the nucleus tractus solitarius, which contains glucosensing neurons, or in ependymal cells lining the third ventricle, where others have described its presence. In the arcuate nucleus, >75% of neuropeptide Y-positive neurons also expressed GK, and most GK+ neurons also expressed KIR6.2 (the pore-forming subunit of the ATP-sensitive K+ channel). The anatomic distribution of GK mRNA was confirmed in micropunch samples of hypothalamus via reverse transcription-polymerase chain reaction (RT-PCR). Nucleotide sequencing of the recovered PCR product indicated identity with nucleotides 1092-1411 (within exon 9 and 10) of hepatic and beta-cell GK. The specific anatomic localization of GK mRNA in hypothalamic areas known to contain glucosensing neurons and the coexpression of KIR6.2 and NPY in GK+ neurons support a role for GK as a primary determinant of glucosensing in neuropeptide neurons that integrate multiple signals relating to peripheral energy metabolism.

Animals↗
PubMed2000

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

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 insulin-induced (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 triphosphate-biotin nick end-labeling (TUNEL) procedure as an index of apoptotic cell death at 24, 48, or 96 h after their first bout. At 48 h, but not 24 h, TUNEL+ cells were consistently seen only in the arcuate nucleus (arcuate hypothalamic nucleus [ARC]). Hypoglycemic rats had 188% more apoptotic ARC cells (1 bout 39+/-5; 3 bouts 37+/-4) than euglycemic controls (13+/-3;P = 0.001). In situ hybridization for neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA was performed in sections of ARC containing maximal numbers of apoptotic cells as well as in other fresh frozen brains. After 1 bout, NPY (0.041+/-0.003) and POMC (0.119+/-0.022) mRNA were decreased, respectively, by 52 and 55% vs. controls (NPY 0.076+/-0.007; POMC 0.222+/-0.020; P = 0.01). NPY (0.029+/-0.002) but not POMC (0.093+/-0.013) fell 29% further after a third bout. NPY (r = -0.721; P = 0.001) and POMC (r = -0.756; P = 0.001) mRNA levels correlated negatively with the number of apoptotic ARC cells in the same sections. Thus, non-coma hypoglycemia produces apparent apoptotic cell death with reduced NPY and POMC expression selectively in the ARC. This may contribute to the reduced counterregulatory response following repeated bouts of hypoglycemia.

Animals↗
PubMed1999

Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats.

The neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus regulate and are regulated by short-term changes in energy homeostasis. Both outbred and inbred strains of rats that develop diet-induced obesity (DIO) or are diet resistant (DR) when fed a diet relatively high in energy, fat, and sucrose content (HE diet) were used to study arcuate NPY mRNA expression during long-term changes in energy balance. Outbred, chow-fed obesity-prone rats had 59% higher NPY levels than obesity-resistant rats. After 14 wk on HE diet, DIO rats had 17% lower NPY levels than DR rats made comparably obese on a highly palatable diet. When switched to chow, obese DR rats spontaneously reduced their intake and their body weights fell to control levels in association with a 10% decrease in NPY levels. DIO rats lost weight only with energy restriction associated with a 21% increase in their NPY levels. When again fed ad libitum, the weight and NPY levels in the rats returned to those of unrestricted DIO rats. Chow-fed, inbred DIO rats weigh more and are fatter than age-matched inbred DR rats. As with outbred DIO rats fed the HE diet, inbred DIO rats had 20% lower NPY levels than DR rats. Thus preobese, outbred DIO rats have high levels of NPY message that are not susceptible to metabolic regulation. When obesity develops in both inbred and outbred rats, the levels of NPY mRNA fall but become responsive to alterations in energy availability.

Animals↗
PubMed1999

Brain glucose sensing and body energy homeostasis: role in obesity and diabetes.

The brain has evolved mechanisms for sensing and regulating glucose metabolism. It receives neural inputs from glucosensors in the periphery but also contains neurons that directly sense changes in glucose levels by using glucose as a signal to alter their firing rate. Glucose-responsive (GR) neurons increase and glucose-sensitive (GS) decrease their firing rate when brain glucose levels rise. GR neurons use an ATP-sensitive K+ channel to regulate their firing. The mechanism regulating GS firing is less certain. Both GR and GS neurons respond to, and participate in, the changes in food intake, sympathoadrenal activity, and energy expenditure produced by extremes of hyper- and hypoglycemia. It is less certain that they respond to the small swings in plasma glucose required for the more physiological regulation of energy homeostasis. Both obesity and diabetes are associated with several alterations in brain glucose sensing. In rats with diet-induced obesity and hyperinsulinemia, GR neurons are hyporesponsive to glucose. Insulin-dependent diabetic rats also have abnormalities of GR neurons and neurotransmitter systems potentially involved in glucose sensing. Thus the challenge for the future is to define the role of brain glucose sensing in the physiological regulation of energy balance and in the pathophysiology of obesity and diabetes.

Animals↗
PubMed1999

Neuropsychological test development and normative data on Hispanics.

The development of culturally relevant psychological assessment tools and intervention procedures has not been commensurate with the rate of Hispanic population growth in the United States. The development of valid and reliable test measures for the assessment of this population must be based on empirical investigations. In this article, we present normative data on multiple measures from the Benton Laboratory and the Wisconsin Card Sorting Test. Results revealed equivalent findings for our Hispanic subjects and the English-speaking samples utilized in the original normative studies within the United States. We additionally review current trends and specific problems encountered in neuropsychological research with Hispanics, and suggest guidelines and directions for future research.

Journal Article↗
PubMed1998

Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain.

Select groups of neurons within the brain alter their firing rate when ambient glucose levels change. These glucose-responsive neurons are integrated into systems which control energy balance in the body. They contain an ATP-sensitive K+ channel (KATP) which mediates this response. KATP channels are composed of an inwardly rectifying pore-forming unit (Kir6.1 or Kir6.2) and a sulfonylurea binding site. Here, we examined the anatomical distribution and phenotype of cells containing Kir6.2 mRNA within the rat brain by combinations of in situ hybridization and immunocytochemistry. Cells containing Kir6. 2 mRNA were widely distributed throughout the brain without apparent concentration in areas known to contain specific glucose-responsive neurons. Kir6.2 mRNA was present in neurons expressing neuron-specific enolase, tyrosine hydroxylase, neuropeptide Y (NPY) and the glutamic acid decarboxylase isoform, GAD65. No astrocytes expressing glial fibrillary acidic protein or oligodendrocytes expressing carbonic anhydrase II were found to co-express Kir6.2 mRNA. Virtually all of the NPY neurons in the hypothalamic arcuate n. and catecholamine neurons in the substantia nigra, pars compacta and locus coeruleus contained Kir6.2 mRNA. Epinephrine neurons in the C2 area also expressed high levels of Kir6.2, while noradrenergic neurons in A5 and A2 areas expressed lower levels. The widespread distribution of Kir6.2 mRNA suggests that the KATP channel may serve a neuroprotective role in neurons which are not directly involved in integrating signals related to the body's energy homeostasis.

Adenosine Triphosphate↗
PubMed1998

Reduced glucose-induced neuronal activation in the hypothalamus of diet-induced obese rats.

Rats predisposed to develop diet-induced obesity (DIO) preferentially activate their sympathetic nervous system during intracarotid glucose infusion [B.E. Levin, Intracarotid glucose-induced norepinephrine response and the development of diet-induced obesity, Int. J. Obesity 16 (1992) 451-457.] but their brains are generally less responsive to glucose than diet-resistant rats (DR) [B.E. Levin, K.L. Brown, A.A. Dunn-Meynell, Differential effects of diet and obesity on high and low affinity sulfonylurea binding sites in the rat brain, Brain Res. 739 (1996) 293-300.; B.E. Levin, B. Planas, Defective glucoregulation of brain alpha2-adrenoceptors in obesity-prone rats, Am. J. Physiol. 264 (1993) R305-R311.; B.E. Levin, A.C. Sullivan, Glucose-induced norepinephrine levels and obesity resistance, Am. J. Physiol. 253 (1987) R475-R481.; B.E. Levin, A.C. Sullivan, Glucose-induced sympathetic activation in obesity-prone and resistant rats, Int. J. Obesity 13 (1989) 235-246.]. Here, 1 h intracarotid glucose infusions (4 mg/kg/min) selectively increased Fos-like immunoreactivity (FLIR) in the hypothalamic paraventricular, ventromedial, dorsomedial and arcuate nuclei of inbred DR but not DIO rats. This suggests that enhanced glucose-induced sympathetic activation in DIO rats is related to a failure of glucose to produce neuronal activation in these areas.

Animals↗
PubMed1998

Norepinephrine and traumatic brain injury: a possible role in post-traumatic edema.

Unilateral cerebral contusion is associated with an early (30 min) increase in norepinephrine (NE) turnover followed by a later (6-24 h) depression of turnover which is bilateral and widespread throughout the brain. Blockade of NE function during the first few hours after traumatic brain injury (TBI) impedes subsequent recovery of function without enlarging the size of the lesion. The current studies were carried out to characterize further the timing of the switch from increased to decreased NE turnover and to investigate the pathogenesis of the delayed recovery of function associated with blocking NE function. Adult male rats had unilateral somatosensory cortex contusions made with a 5 mm diameter impact piston. They were killed after 2 h and their brains analyzed for NE turnover by HPLC with electrochemical detection. In general, NE turnover (the ratio of 3-methoxy-4-hyroxyphenylglycol to NE levels) had returned to sham-lesion control levels in most brain regions by 2 h after either left or right sided contusions. The only exceptions were a persistent 87% increase at the lesion site after right-sided contusions and 22% and 32% increases in the contralateral cerebellum after right- and left-sided contusions, respectively. Blockade of alpha1-adrenoceptors by treatment with prazosin (3 mg/ kg, i.p.) 30 min prior to TBI produced edema in the striatum and hippocampus at 24 h which was not seen saline-treated rats nor in rats where NE reuptake was blocked with desmethylimipramine (DMI; 10 mg/kg, i.p.). DMI increased edema at the lesion site at 24 h, however. These data suggest that the early increase in NE release following unilateral cerebral contusion is protective and that this may act to stabilize the blood-brain barrier in areas adjacent to the injury site. Drugs that interfere with this enhanced noradrenergic function might enhance the damage caused by TBI.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Insulin selectively downregulates alpha2-adrenoceptors in the arcuate and dorsomedial nucleus.

Intracerebroventricular infusion of insulin (2 mU/ day) produced selective downregulation of 3H-paraminoclonidine binding to alpha2-adrenoceptors in the hypothalamic arcuate (14%) and dorsomedial (19%) nuclei out of 16 forebrain areas in Wistar rats. Binding of 3H-prazosin to alpha1-adrenoceptors was unaffected. This is in keeping with the known effect of insulin on catecholamine and neuropeptide Y metabolism in these brain regions that play an important role in energy homeostasis.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

Effect of streptozotocin-induced diabetes on rat brain sulfonylurea binding sites.

Both high and low affinity sulfonylurea receptors (SURs) reside on glucose responsive neurons where they influence cell firing and neurotransmitter release via the adenosinetriphosphate (ATP)-sensitive K+ (katp) channel. Here, the effect of diabetes on [3H] glyburide binding to SURs was assessed in male obesity-resistant Sprague-Dawley rats rendered diabetic with streptozotocin (65 mg/kg, i.p.). Additional streptozotocin-treated rats were supplemented with insulin (1.5 U/kg/ day). Streptozotocin reduced plasma insulin to 13% of control associated with hyperglycemia (25.3 +/- 1.7 mmol/l), while insulin lowered plasma glucose (9.56 +/- 1.78 mmol/l) to near control levels (7.65 +/- 0.22 mmol/l). Over 7 days, all streptozotocin-treated rats lost 12% of their initial body wt. while controls gained 1%. Despite equivalent wt. loss, streptozotocin-induced diabetes selectively increased high affinity [3H] glyburide binding in the hypothalamic dorsomedial nuclei (DMN) and ventromedial nuclei (VMN) and lateral area (LH). This was prevented by insulin injections. Low affinity binding was similarly increased in the DMN and VMN, as well as two amygdalar subnuclei but decreased in the substantia nigra, pars compacta. Insulin fully prevented these changes only in the DMN and one amygdalar nucleus and the substantia nigra. Therefore, binding to (SURs) appears to be generally upregulated in the face of hypoinsulinemia with hyperglycemia and this is prevented by insulin treatment. These and other data suggest that this combination of abnormalities in diabetes should have an adverse effect on the glucose sensing capacity of the brain.

Amygdala↗
PubMed1998

Defense of differing body weight set points in diet-induced obese and resistant rats.

Among outbred Sprague-Dawley rats, approximately one-half develop diet-induced obesity (DIO) and one-half are diet resistant (DR) on a diet relatively high in fat and energy content (HE diet). Here we examined the defense of body weight in these two phenotypes. After HE diet for 13 wk, followed by chow for 6 wk, DR rats gained weight comparably but their plasma leptin levels fell to 54% of chow-fed controls. When a palatable liquid diet (Ensure) was added for 13 wk, other DR rats became obese. But when switched to chow, their intakes fell by 60%, and body and retroperitoneal (RP) fat pad weights and plasma leptin and insulin levels all declined for 2 wk and then stabilized at control levels after 6 wk. In contrast, comparably obese DIO rats decreased their intake by only 20%, and their weights plateaued when they were switched to chow after 13 wk on HE diet. When a subgroup of these DIO rats was restricted to 60% of prior intake, their weights fell to chow-fed control levels over 2 wk. But their leptin and insulin levels both fell disproportionately to 30% of controls. When no longer restricted, their intake and feed efficiency rose immediately, and their body and RP pad weights and leptin and insulin levels rose to those of unrestricted DIO rats within 2 wk. Thus diet and genetic background interact to establish high (DIO) or low (DR) body weight set points, which are then defended against subsequent changes in diet composition and/or energy availability. If leptin affects energy homeostasis, it does so differentially in DIO vs. DR rats since comparably low and high levels were associated with differing patterns of weight change between the two phenotypes.

Animals↗
PubMed1998

Gestational obesity accentuates obesity in obesity-prone progeny.

Maternal obesity and genetic background can affect the development of obesity and diabetes in offspring. Here we used selected strains of rats resistant (DR) vs. susceptible to development of diet-induced obesity (DIO) on high-energy (HE) diets to assess this issue. DR and DIO dams were fed either Chow or HE diet for 4 wk. DIO HE diet-fed dams and additional DR rats fed a palatable liquid diet (Ensure) became more obese and hyperinsulinemic than the other groups. During lactation, all dams were fed their respective diets, and offspring were fed Chow from weaning to 16 wk of age. All offspring of DIO dams gained more weight and had heavier retroperitoneal fat pads and higher leptin levels than DR progeny, but offspring of the more obese DIO HE dams had heavier fat pads and higher glucose levels than DIO Chow offspring. After 4 wk on HE diet, all DIO offspring gained more weight and had heavier total adipose depots and higher insulin and leptin levels than DR offspring. Offspring of DIO HE dams also gained more weight and had heavier fat depots and higher leptin levels than DIO Chow offspring. Therefore maternal obesity and hyperinsulinemia were associated with increased obesity in those offspring already genetically predisposed to become obese.

Animal Feed↗
PubMed1998

Age of disease onset influences cognition in Parkinson's disease.

It is controversial whether age of disease onset is related to cognitive decline in Parkinson's disease (PD). We administered 7 cognitive measures assessing visuospatial skills, memory, and executive functions to 222 patients with idiopathic PD and 108 normal control participants. Regression analyses demonstrated that older age of disease onset consistently predicted cognitive decline above and beyond normative aging and duration of illness. These findings suggest that older age of disease onset is a critical determinant of cognitive deterioration in PD.

Age of Onset↗
PubMed1997

Phosphorylation modulates the activity of the ATP-sensitive K+ channel in the ventromedial hypothalamic nucleus.

Regulation of the ATP-sensitive K+ (K-ATP) channel was examined in cell-attached and inside-out membrane patches of freshly isolated neurons from the ventromedial hypothalamic nucleus (VMN) of 7-14 day old male Sprague-Dawley rats. When inside-out patches were exposed to symmetrical K+, the reversal potential was -2.85 +/- 1.65 mV, the single channel conductance 46 pS, and the total conductance varied as a multiple of this value. Glucose (10 mM) reversibly inhibited channel activity in cell-attached preparations by 81%. In the presence of 0.1 mM ADP, 10, 5, and 1 mM ATP reversibly inhibited VMN K-ATP channels in inside-out patches by 88, 83, and 60%, respectively. This inhibition was not dependent on phosphorylation since 5 mM AMPPNP, the non-hydrolyzable analog of ATP, reversibly inhibited channel activity by 67%. Relatively high concentrations of glibenclamide (100 microM) also reversibly inhibited VMN K-ATP channel activity in cell attached and inside-out patches by 67 and 79%, respectively. Finally, the non-specific kinase inhibitor H7 (200 microM) decreased channel activity by 53% while the non-specific phosphatase inhibitor microcystin (250 nM) increased channel activity by 218%. These data suggest that while the inhibitory effect of ATP is not phosphorylation dependent, phosphorylation state is an important regulator of the VMN K-ATP channel.

Adenosine Triphosphate↗
PubMed1997

In vivo and in vitro regulation of [3H]glyburide binding to brain sulfonylurea receptors in obesity-prone and resistant rats by glucose.

Select brain neurons increase their firing rate when ambient glucose levels rise, possibly via a neuronal ATP-sensitive K+ (KATP) channel and its associated sulfonylurea receptor (SUR). We used receptor autoradiographic binding of 20 nM [3H]glyburide (in the presence or absence of Gpp(NH)p which blocks binding to low-affinity sites) to assess the in vivo and in vitro effects of altering glucose availability upon high- and low-affinity binding to brain SUR. Since the brain's ability to monitor and regulate glucose metabolism is critical to maintenance of energy balance, testing was done in chow-fed male Sprague-Dawley rats which had an underlying predisposition to develop either diet-induced obesity (DIO-prone) or to be diet-resistant (DR-prone) when subsequently fed a high-energy diet. Under control conditions, both in vivo and in vitro studies showed DIO-prone rats to have reduced levels of low-, but not high-affinity [3H]glyburide binding in most forebrain areas. As compared to equiosmolar infusions of mannitol, 60 min unilateral intracarotid glucose infusions at 4 mg/kg/min in awake rats reduced low-affinity [3H]glyburide binding in numerous hypothalamic and amygdalar areas of both DR- and DIO-prone rats with little effect on high-affinity binding. Only in the paraventricular nucleus of DR-prone rats was there a phenotype-specific downregulation of low-affinity binding. Brain sections from other rats were incubated with [3H]glyburide in the presence of 0, 5 or 10 mM glucose. The resultant in vitro effects of glucose were more variable and widespread than intracarotid infusions. Here, glucose often increased low-affinity [3H]glyburide binding, particularly in DR-prone rats at 5 mM. Again, there was little effect on high-affinity binding. Thus, glucose may affect the firing of glucose-responsive neurons by indirectly altering KATP channel function via its effects on low-affinity cell body SUR.

ATP-Binding Cassette Transporters↗
PubMed1997

Histological markers of neuronal, axonal and astrocytic changes after lateral rigid impact traumatic brain injury.

The model of lateral, rigid impact traumatic brain injury is widely used but remains relatively poorly characterized by comparison with fluid percussion injury models. Thus, whilst the gross morphological changes that occur over the short- and long-term post-injury have been described, more subtle measures of neuronal injury and activation, and markers of axonal and glial reactions have not been investigated, complicating interpretation of data from this model. To address this issue, a variety of neurohistological markers were examined in adult male rats which had been subjected to open brain, lateral rigid impact injury. A piston device was unilaterally driven 3.0 mm into the somatosensory cortex at a speed of 3.2 m/s. Neuronal activation evidenced by Fos-like immunoreactivity showed a complex pattern at 3 h after injury which appeared to be related both to proximity to the impact site and cortical efferent connectivity. At 24 h after injury, acid fuchsin staining demonstrated dying neurons in the margin of the injury and in ipsilateral hippocampus and dorsal thalamus. Injured cells identified by heat-shock protein immunoreactivity showed a similar distribution. Axonal injury demonstrated with 68 kDa neurofilament immunoreactivity was more widely distributed. Less axonal damage was found with increasing distance from the injury site. At 7 days post-injury, glial fibrillary acidic protein immunoreactive astrocytes were prolific in the ipsilateral thalamus, hippocampus and striatum and throughout the injured cortex. In general, controlled, lateral rigid impact injury provides a more focused injury than is seen with lateral fluid percussion which may have implications for the behavioral deficits seen in this injury model.

Animals↗
PubMed1997

Intracarotid glucose selectively increases Fos-like immunoreactivity in paraventricular, ventromedial and dorsomedial nuclei neurons.

Perfusion of the forebrain with glucose at concentrations which alter neither plasma insulin nor glucose levels leads to sympathetic activation in some rats. We used the expression of Fos-like immunoreactivity (FLI) as an index of neuronal activation to examine the anatomic substrate underlying this phenomenon. Male Sprague-Dawley rats were infused via the right internal carotid artery with glucose (4 mg/kg/min) or equiosmolar mannitol for 60 min. They were killed 3 h after infusion onset and their brains reacted for FLI. As compared to mannitol-infused controls, 105% and 117% more neurons in hypothalamic ventromedial nucleus (VMN) and parvocellular portion of the paraventricular nuclei (PVN) of glucose-infused rats showed FLI, respectively. Importantly, only about half the glucose-infused rats showed increased FLI cells in these areas when compared to controls. In these same animals, glucose also significantly activated cells in the dorsomedial n. There was little FLI expressed in the magnocellular neurons of the PVN. This selective glucose response was bilateral in keeping with the bilateral distribution of India ink to midline hypothalamic structures following unilateral carotid infusions. Retrograde transport of cholera toxin B from medullary and thoracic spinal cord sympathetic outflow areas showed labeling of about 10% of PVN neurons with FLI activated by intracarotid glucose. There was no double labeling of VMN neurons. This supports the presence of anatomic pathways by which a subpopulation of glucose responsive PVN neurons might activate the sympathetic outflow areas in the medulla and spinal cord. The apparent bimodal distribution of glucose-induced activation of VMN and PVN neurons is in keeping with a similar bimodal pattern of sympathetic activation which obesity-prone but not obesity-resistant rats show following glucose infusions. Taken together, these data support a role for glucose-sensitive VMN and parvocellular PVN neurons in the weight gain phenotype specific sympathetic activation to glucose.

Animals↗