Neuropeptide Y, peptide YY and aluminum in Alzheimer's disease: is there an etiological relationship?

Neuropeptide Y (NPY) and peptide YY (PYY) are members of the pancreatic polypeptide family which have a high degree of primary and tertiary structural homology. They function as neurotransmitters and humoral agents in central nervous system and gastrointestinal function. During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease. Recent research has shown that both NPY and PYY may be involved in aluminum metabolism in animal models. A brief discussion of the structure, biological activity and possible involvement of these peptides in aluminum metabolism and Alzheimer's disease is contained herein.

In ovo peptide YY and epidermal growth factor administration and their effects on growth and yolk utilization in neonatal meat-type chickens (Gallus domesticus).

The effects of in ovo peptide YY (PYY) or epidermal growth factor (EGF) administration on chick growth, yolk absorption and yolk stalk function in posthatch (0-5 days) meat-type or broiler chicks were determined. At Day 18 of incubation, treated eggs were injected into the air cell with 100 microl of either PYY (Trial 1) or EGF (Trial 2) at a dosage of 600 microg/kg egg weight. Saline-treated control eggs were injected similarly with 0.9% saline. At hatch, 200 microl of (51)Cr-labeled microspheres were injected into chick yolk sacs. Epidermal growth factor increased ileal wet weight adjusted for body weight as well as ileal serosal dry matter. Body weight, feed consumption and excreta weight per bird, and relative weights of the yolk sac, intestine and liver were significantly affected by age of the chick in both trials. Relative radioactivity of the yolk sac, yolk stalk, blood, liver, and kidneys were affected by bird age in Trial 2; however, there were no significant effects due to PYY or EGF treatments on relative radioactivity of the tissues and organs examined. These data suggest that PYY and EGF had no effect on yolk absorption or yolk stalk function through 5 days in the posthatch chick.

Peptide YY administration decreases brain aluminum in the Ts65Dn Down syndrome mouse model.

We have previously reported the Ts65Dn (Ts) mouse has impaired intestinal absorptive function and amino acid metabolism. Peptide YY (PYY) has enhanced glucose absorption in mice and turkeys. Other studies have reported that persons with Down syndrome have increased intestinal absorption of aluminum. Alzheimer's-like lesions have been reported in Ts mice. Trial 1 of this study examined brain Al concentrations, plasma metabolites and intestinal metabolism of 40 control and 40 Ts mice administered 300microg PYY/kg body weight or 0.9% saline for 3d. Trial 2 examined nutrient digestibility of 12 C and 12 Ts given PYY or saline for 14d. In Trial 1, PYY lowered (p<0.05) the brain Al pool (mg/g FBW) in both C and Ts mice by 80% compared to saline. Ts mice had increased plasma NH3 (329 vs. 269 microM, p<0.05), decreased plasma glucose (7.4 vs. 8.4 mM, p<0.01), elevated apparent energetic efficiency of jejunal glucose uptake (p<0.01) and elevated brain Al pool (0.41 vs. 0.12 microg, p=0.06) compared to C mice. In Trial 2, PYY increased small intestinal density (mg/cm) 12% in both genotypes (p<0.05), but did not alter nutrient digestibility. Brain Al accretion and hyperammonemia are proposed risk factors for Alzheimer's disease (AD). Ts mice and PYY appear to be suitable models for the study of metabolic and neurological anomalies in Down syndrome and AD.

In ovo peptide YY administration improves growth and feed conversion ratios in week-old broiler chicks.

The effects of in ovo Peptide YY (PYY) administration on growth and feed conversion ratios in a commercial broiler line were investigated. Six hundred Ross male x Cobb female eggs were administered either 0.9% saline (control) or 600 microg/kg egg weight PYY in ovo at Day 18 of incubation. On day of hatching, 210 birds from each treatment group were randomly placed by sex into pens. Body weights at placement were not different between treatment groups. Average chick body weight and adjusted pen feed conversion ratios were improved by PYY in ovo treatment at 7 d posthatch (165.7 vs. 170.2 g, P<0.02; and 1.55 vs. 1.49, P<0.04, respectively). No significant differences between treatments were noted for these parameters at 21 or 42 d of age. These results suggest that in ovo treatment of broiler chicken eggs with gastrointestinal hormones that increase intestinal nutrient absorption, such as PYY, may enhance chick performance.

Jejunal function and plasma amino acid concentrations in the segmental trisomic Ts65Dn mouse.

Mice trisomic for the distal portion of MMU 16 (Ts65Dn) were examined for differences in jejunal function and plasma amino acids as compared to diploid controls. Eighteen control and 19 Ts65Dn mice were compared for whole-body and intestinal O2 consumption, jejunal glucose uptake, and plasma amino acid concentrations. Ts65Dn mice consumed less (P < 0.02) O2 per gram of fasted body weight. No significant differences were found in either active or passive glucose uptake. Oxygen consumption by jejunal tissue was not different between Ts65Dn and control mice. The apparent energetic efficiency of jejunal active glucose uptake (eta mol ATP expended/eta mol glucose uptake) was significantly higher (115.6 vs. 80.8; P < 0.05) in Ts65Dn mice. Histomorphometric analysis of jejunal mucosa showed that Ts65Dn mice had shorter villus height (P < 0.04) and decreased planar villus circumference (P = 0.05). No differences were found in total jejunal protein (microgram/g) or DNA (mg/g) concentrations. Significantly higher concentrations of plasma tyrosine, phenylalanine, valine, leucine, isoleucine, and citrulline (P < 0.05) were found in Ts65Dn mice. Lower plasma concentrations of hydroxyproline were detected in Ts65Dn mice (P < 0.05). These data suggest that Ts65Dn mice have anomalies in digestive function and amino acid metabolism as compared to normal, diploid controls.

RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient beta-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice.

OBJECTIVE: To investigate the role of hypercorticism in the development of compromised beta-adrenergic signalling in adipocytes of mature C57BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mice and their lean littermates were treated with vehicle or the specific glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte Gs alpha expression, adenylylcyclase activation by beta-adrenergic receptor (beta-AR) agonists in adipocyte membranes and mRNA levels for beta 1-, beta 2- and beta 3-adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels in ob/ob mice to levels that were not different from lean mice. RU-486 also reduced serum insulin by approximately 50% in ob/ob mice, but failed to restore depressed Gs alpha or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in beta 3-AR mRNA in ob/ob mice and a small but significant improvement in isoprenaline-mediated adenylylcyclase activation. CONCLUSIONS: The present results indicate that glucocorticoid antagonism ameliorates diabetic symptoms of the mature ob/ob mouse, but does not lessen their obesity or fully reverse deficient expression and function of components of the adipocyte beta-adrenergic signalling cascade.

Adrenalectomy after weaning restores beta3-adrenergic receptor expression in white adipocytes from C57BL/6J-ob/ob mice.

The role of hypercorticism in the development of compromised beta-adrenergic signaling in adipose tissue was assessed in ob/ob mice adrenalectomized at 4 weeks of age and studied 1 and 3 weeks thereafter. Adrenalectomy prevented the rapid increase in body weight and fat deposition between 4 and 5 weeks of age in ob/ob mice and produced a phenotype indistinguishable from that of lean mice. However, adrenalectomized ob/ob mice became intermediate between lean and ob/ob mice by 7 weeks of age. Adipocyte beta3-adrenergic receptor (AR) messenger RNA levels were similar between lean and adrenalectomized ob/ob mice at both time points and were 4- to 8-fold higher than messenger RNA levels in ob/ob mice. As judged by maximal activation of adenylyl cyclase by a beta3-AR-selective agonist, adrenalectomy also restored functional activity of the beta3-AR to levels above or equivalent to those seen in lean mice at both time points. The present results suggest that development of hypercorticism at or before weaning in ob/ob mice represses expression of the beta3-AR and prevents the normal postweaning development of this signaling system in the adipocyte.

Distribution of pancreatic polypeptide receptors in the rat brain.

Pancreatic polypeptide (PP) is a regulatory peptide that modulates gastrointestinal function. Previously we demonstrated PP receptors in the brainstem and interpeduncular nucleus, and the PP receptors in the brainstem appear to modulate gastric motility and pancreatic exocrine secretion. The purpose of this study is to extend our understanding of the distribution of PP receptors in the rat brain in order to determine the systems that are potentially modulated by PP. Rat brains were studied using 125I-PP receptor autoradiography on cryostat sections of the entire brain cut in three planes (horizontal, sagittal, and coronal). Brain regions exhibiting PP binding sites were confirmed when identified in all three planes of section. Saturable PP binding was identified in the hypothalamus (arcuate and paraventricular n), the rostral forebrain (medial preoptic area, anterior olfactory nucleus, islands of Calleja, the dorsal endopiriform n, piriform cortex, and the bed n of the stria terminalis), medial amygdaloid n; the thalamus (anteromedial thal. n; reuniens thal. n; and paraventricular thal n), the interpeduncular red nucleus, substantia nigra, parabrachial n; locus coeruleus, mesencephalic trigeminal n, dorsal motor n of the vagus, the n solitary tract, and the area postrema. We conclude that PP receptors are distributed widely throughout the rat brain. The distribution of many of these PP binding sites corresponds to brain regions regulating digestion and autonomic function. We speculate, based on the patterns of binding in the olfactory and limbic systems, that PP receptors might be involved in positive reinforcement of ingestion behavioral as well as modulation of gastrointestinal function.

Peptide regulation of intestinal glucose absorption.

Terminal hydrolysis of oligosaccharides at the small intestinal brush border yields monomeric glucose, most of which is then absorbed by the transepithelial route. This involves carrier-mediated processes requiring specialized functional proteins situated in the brush border (SGLT1) and basolateral (GLUT2) membranes. Glucose translocation at the enterocyte apical membrane is an active, Na(+)-dependent and saturable process, whereas exit from enterocytes is by facilitated diffusion and is energy-independent. Specific adaptation of glucose active transport occurs in response to changes in the proportion of glucose in the diet. The regulatory signals responsible for transport induction are imprecisely defined, although numerous protein hormones and gut regulatory proteins are implicated. Epidermal growth factor and peptide YY invoke up-regulation of jejunal active glucose transport in vivo. Recently, peptide YY has been shown to stimulate active glucose transport in mice without altering oxygen consumption of jejunal tissue. Several other peptides whose presence in tissues of the small bowel imply that they exert control over epithelial nutrient transport are considered, and the relevance of these physiological manipulations, with various regulatory peptides and hormones, to animal agriculture are discussed.

Apolipoprotein A-IV acts in the brain to inhibit gastric emptying in the rat.

We have very recently shown that intracisternal injection of apolipoprotein A-IV (apo A-IV), a glycoprotein produced in the small intestine by fat, dose-dependently inhibited gastric acid secretion in pylorus-ligated conscious rats. These results suggest that apo A-IV acts centrally as a neuromodulator to inhibit gastric secretion. The present study was carried out to examine the hypothesis that apo A-IV acts centrally to alter gastric emptying. Rats fasted 24 h received intracisternal injection of apo A-IV and a liquid meal by oral intubation under brief isoflurane anesthesia. Gastric emptying of a liquid meal was determined by the phenol red method. Intracisternal injection of apo A-IV inhibited gastric emptying of a liquid meal in a dose-dependent manner (1.0-4.0 micrograms). On the other hand, apo A-I in a dose of 4 micrograms failed to change gastric emptying. Gastric emptying was not altered by intraperitoneal administration of apo A-IV in a dose of 15 micrograms. These results suggest that apo A-IV acts centrally to delay gastric emptying of a liquid meal. Together with our recent finding that apo A-IV acts centrally to inhibit gastric acid secretion, the present study supports our hypothesis that apo A-IV may be involved in lipid-induced inhibition of gastric function.

Mechanism of action of intracisternal apolipoprotein A-IV in inhibiting gastric acid secretion in rats.

BACKGROUND & AIMS: We recently showed that intracisternal injection of apolipoprotein A-IV (apo A-IV), a protein produced by the small intestine in response to fat, inhibits gastric acid secretion. The aim of this study was to investigate the mechanism of acid inhibition by central apo A-IV. METHODS: Gastric acid secretion was determined in pylorus-ligated conscious rats. The effect of intracisternal injection of apo A-IV on gastric acid secretion stimulated by pentagastrin, bethanechol, or intracisternal thyrotropin-releasing hormone (central vagal stimulant) was examined. The effects of vagotomy, indomethacin, and adrenergic blockers on the acid inhibition of apo A-IV were examined to investigate the role of the vagal system, prostaglandin pathways, and adrenergic system. RESULTS: Intracisternal apo A-IV significantly inhibited pentagastrin-, bethanechol-, and thyrotropin-releasing hormone-stimulated gastric acid secretion in a similar fashion. Inhibition of pentagastrin-stimulated acid secretion by apo A-IV still occurred even in vagotomized rats. Yohimbine but not indomethacin or propranolol eliminated apo A-IV--induced inhibition of acid. CONCLUSIONS: Intracisternal apo A-IV inhibits gastric acid secretion through alpha 2-adrenergic receptors. The vagal pathway and the prostaglandin system are not involved in apo A-IV--induced acid inhibition.

Microinjection of TRH analogue into the dorsal vagal complex stimulates pancreatic secretion in rats.

Thyrotropin-releasing hormone (TRH) stimulates pancreatic exocrine secretion through the vagus nerve when injected into rat cerebrospinal fluid. However, little is known about the exact site of action of TRH in the brain to stimulate pancreatic secretion. Recent neuroimmunochemical and neurophysiological studies suggest that TRH could be a neurotransmitter in the dorsal vagal complex, which sends fibers to the pancreas through the vagus nerve. We therefore hypothesized that TRH may act centrally in the dorsal vagal complex to stimulate pancreatic exocrine secretion. To address this question, a TRH analogue, [1-methyl-(S)-4,5-dihydroorotyl]-L-histidyl-L-prolinamide- NH2, was microinjected into the dorsal vagal complex, and basal pancreatic fluid flow and protein secretion were measured in urethan-anesthetized rats. Microinjection of TRH analogue (0.2-2 ng/site) into the dorsal vagal complex significantly stimulated pancreatic flow and protein output in a dose-dependent manner. As a control, microinjection of the TRH analogue into the brain stem outside the vagal complex failed to stimulate pancreatic secretion. Either bilateral subdiaphragmatic vagotomy or atropine abolished the ability of the TRH analogue to stimulate pancreatic secretion. Our data suggest that TRH acts in the dorsal vagal complex to stimulate pancreatic secretion through vagus-dependent and cholinergic pathways. The dorsal vagal complex may play an important role as a central site for control of the exocrine pancreas.

Tissue-specific alterations in G protein expression in genetic versus diet-induced models of non-insulin-dependent diabetes mellitus in the mouse.

Various tissues were obtained from the well-characterized genetic model (C57BL/6J-ob/ob) of non-insulin-dependent diabetes mellitus (NIDDM) and from a diet-induced model of NIDDM produced in the same genetic background (C57BL/6J). The objectives were to determine whether the previously observed changes in guanine nucleotide-binding regulatory protein (G protein) expression in adipose tissue from ob/ob mice were mirrored by concomitant changes in other tissues, and whether NIDDM of a different etiology would share similar alterations in G protein expression. Plasma membranes from adipocytes, brain, heart, liver, and testes were probed with alpha-subunit-specific antisera, and the level of G protein expression in each model was compared with that in its lean littermate control. Adipose, heart, and liver cell membranes from ob/ob mice contained significantly less alpha-subunit of stimulatory G protein (Gs alpha) than those from their lean littermates. As compared with the lean littermates, heart alpha-subunit-2 of inhibitory G protein (Gi alpha-2), liver Gi alpha-3, and adipocyte G1 alpha-1 and Gi alpha-3 were also reduced in ob/ob mice. In contrast, Gi alpha-2 and Go alpha were increased over lean-control levels in brain tissue from ob/ob mice, whereas Gs alpha was unchanged. G protein expression in the testes did not differ between lean and ob/ob mice. In the diet-induced model of NIDDM, Gs alpha expression in the liver was twofold greater in obese/diabetic mice as compared with lean controls. However, G protein expression in all other tissues examined did not differ between obese/diabetic animals and lean littermates.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic polypeptide microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats.

BACKGROUND/AIMS: Pancreatic polypeptide (PP), a hormone released from the pancreas, inhibits pancreatic secretion in vivo but not in vitro, suggesting that the inhibitory action of PP on pancreatic secretion is indirect. Circulating PP in physiological concentrations binds to specific receptors in the dorsal vagal complex in the brainstem. Therefore, the hypothesis of this study was that PP acts centrally and inhibits pancreatic secretion by modulating vagal tone. METHODS: The effects of microinjection of PP into the dorsal motor nucleus on 2-deoxy-D-glucose-stimulated and cholecystokinin octapeptide (CCK-8)-stimulated pancreatic secretion were examined in urethane-anesthetized rats. RESULTS: Microinjection of PP to the dorsal motor nucleus but not brainstem sites outside it inhibited 2-deoxy-D-glucose-stimulated pancreatic flow and protein output. CCK-8-stimulated pancreatic protein output was inhibited by PP in the dorsal motor nucleus in dose-dependent and site-specific manners. The inhibitory effect of PP on CCK-8-stimulated protein output was eliminated by vagotomy. CONCLUSIONS: The results suggest that PP acts in the dorsal motor nucleus to modulate vagal tone on the pancreas, thereby inhibiting pancreatic secretion. This study shows for the first time that the dorsal motor nucleus is involved in central feedback inhibition of the exocrine pancreas.

Age-dependent changes in beta-adrenergic receptor subtypes and adenylyl cyclase activation in adipocytes from Fischer 344 rats.

Epididymal adipocytes were isolated from Fischer 344 rats aged 3, 6, 12, and 24 months, to study the mechanisms responsible for age-dependent diminution in cellular adrenergic responsiveness. Messenger RNA (mRNA) levels for the beta 1-, beta 2-, and beta 3-adrenergic receptors (ARs) were compared across age groups and related to adenylyl cyclase activation by selective receptor agonists in adipocyte plasma membranes and activation of lipolysis in intact cells. mRNA levels for the beta 1-AR decreased by 60% between 3-6 months and remained at this reduced level through 12 and 24 months. A modest increase in beta 2-AR mRNA was noted between 3-12 months, but decreased between 12-24 months to levels seen in the 3-month-old group. mRNA for the beta 3-AR did not change between 3-6 months, but decreased by about 40% between 6-12 months, and by a further 50% between 12-24 months. Lipolytic responsiveness also diminished with age, and regardless of whether beta 3-selective or beta 1/beta 2-selective agonists were used, the maximal release of glycerol was most severely blunted in adipocytes from 24-month-old rats. The age-dependent changes in adenylyl cyclase activation by beta-adrenergic agonists mirrored the observed changes in lipolytic responsiveness with respect to diminished efficacy. These results together with the similar forskolin-stimulated adenylyl cyclase activity among the groups suggest age-dependent changes in activation of adenylyl cyclase at a prior step. This suggestion is also supported by the comparable inhibitory capacities of the alpha 2-adrenergic and A1-adenosine signaling systems among the age groups. In view of the similar levels of Gs alpha, the age-dependent decrease in adrenergic responsiveness in rat adipocytes appears to result primarily from specific decreases in the expression of both beta 3-AR and beta 1-ARs.

Intracisternal injection of TRH antibody blocks gastric emptying stimulated by 2-deoxy-D-glucose in rats.

We evaluated the effect of 2-deoxy-D-glucose (2-DG) on gastric emptying of a non nutrient solution in conscious rats using a Phenol red method. Intravenous injection of 2-deoxy-D-glucose dose-dependently increased the rate of gastric emptying. This stimulatory action of 2-DG was abolished by subdiaphragmatic vagotomy. Intracisternal injection of thyrotropin-releasing hormone (TRH) antibody blocked intracisternal TRH and intravenous 2-DG-induced enhancement of gastric emptying but not the stimulation of gastric emptying induced by intracisternal pancreatic polypeptide. The TRH antibody injected intraperitoneally had no effect. These results suggest that endogenous TRH in the brain is involved in vagal-dependent stimulation of gastric emptying by 2-DG.

Apolipoprotein A-IV acts centrally in the brain to reduce the severity of gastric ulceration in the rat.

We have recently reported that apolipoprotein A-IV (apo A-IV), a protein associated with lipoproteins, acts in the brain to inhibit gastric acid secretion. In the present study, we determined whether or not apo A-IV has an anti-ulcer action via the central nervous system using Sprague-Dawley rats. Intracisternal injection of apo A-IV dose-dependently (2.0-4.0 micrograms/rat) reduced the severity of gastric mucosal lesions induced by intravenous injection of 2-deoxy-D-glucose or subcutaneous administration of indomethacine. A higher dose (15 micrograms) of apo A-IV injected intraperitoneally failed to inhibit the development of gastric mucosal damage evoked by these ulcerogenic agents. These results suggest for the first time that apo A-IV has an anti-ulcer action through a central mechanism.

Gastric mucosal damage induced by 2-deoxy-D-glucose involves medullary TRH in the rat.

These studies examined the effect of 2-deoxy-D-glucose (2-DG) on gastric mucosal integrity. Intravenous administration of 2-DG in doses of 100 and 125 mg/kg dose-dependently produced multiple, hemorrhagic gastric mucosal lesions while 75 mg/kg of 2-DG failed to induce gastric lesions. Intracisternal injection of 2-DG in doses of 10 and 20 mg/kg also induced gastric mucosal damage in a dose-dependent manner whereas the injection of 5 mg/kg of 2-DG intracisternally did not induce the development of gastric lesions. Gastric mucosal damage by intravenous 2-DG was completely blocked by bilateral gastric branch vagotomy. Intracisternal but not intraperitoneal injection of anti-TRH antibody 8964 significantly reduced the severity of gastric mucosal lesions evoked by intravenous administration of 2-DG. These results suggest that 2-DG acts in the brain to induce gastric mucosal damage through vagal dependent pathways. Endogenous TRH in the central nervous system may be involved in the production of gastric mucosal damage by 2-DG.

Intracisternal injection of apolipoprotein A-IV inhibits gastric secretion in pylorus-ligated conscious rats.

BACKGROUND/AIMS: Fat feeding increases not only serum but also cerebrospinal fluid concentration of apolipoprotein (apo) A-IV, a protein produced mainly by the small intestine in the rat. We hypothesized that apo A-IV may have a central effect on gastric secretion. METHODS: Gastric juice was collected by the pylorus ligation method. Rats underwent pylorus ligation and received intracisternal injection of apo A-IV under brief isoflurane anesthesia. Two hours after the injection, gastric juice was collected and gastric acid output determined. RESULTS: Intracisternal injection of 0.5 microgram apo A-IV had no effect on gastric secretion. However, gastric acid secretion was significantly inhibited by intracisternal injection of 1 microgram apo A-IV. Furthermore, intracisternal administration of higher doses of apo A-IV (2.0 and 4.0 microgram) resulted in greater inhibition of gastric acid secretion in a dose-dependent manner. On the contrary, 4 micrograms of apo A-I intracisternally injected failed to inhibit gastric acid secretion. Intraperitoneal administration of 15 micrograms of apo A-IV did not alter gastric secretion. CONCLUSIONS: These results suggest that apo A-IV may act in the brain to inhibit gastric acid secretion. Apo A-IV might be a central enterogastrone, which is a gastric inhibitor produced by the small intestine in response to fat feeding.