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Biomedical subjects

L Brunner

Publications and source records attributed to L Brunner.

At least 19 recordsLinked to original sources
PubMed1999

A peptide leptin antagonist reduces food intake in rodents.

OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into ob/ob and into db/db mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in ob/ob mice and, like leptin, was inactive after i.p. injection to db/db mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

Animals↗
PubMed1998

Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor.

The new neuropeptide Y (NPY) Y5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y5 subtype, but > 1, 000-fold lower affinity for the cloned rat NPY Y1, Y2, and Y4 subtypes. In LMTK cells transfected with the human NPY Y5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given intraperitoneally (dose range 1-100 mg/kg) to a series of animal models of high hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 71683A dose-dependently inhibited food intake. During the dark phase, CGP 71683A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4. Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The data demonstrate that the NPY Y5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulatory mechanisms are induced to restore appetite.

Animals↗
PubMed1998

The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes.

Thirteen neuropeptide Y (NPY) agonists were administered intracerebroventricularly (i.c.v.) in rats (full dose-response curves) to estimate their half-effective dose (ED50) on feeding. These values were compared to their binding affinities (IC50) for rat NPY receptor subtypes Y1, Y2, Y4 and Y5 in vitro. Correlations between in vivo ED50 and in vitro IC50 were strong for the Y5 (r = 0.87; P < 0.01), weak for the Y1 (r = 0.48; P < 0.04) and non-significant for the Y2 and Y4 receptor subtypes. In vitro, h[D-Trp32]NPY was found to be a Y5-selective ligand and a full agonist in Y5-expressing cells. In vivo, it dose-dependently stimulated feeding, but failed to induce the full maximal response observed with pNPY. It did not antagonize pNPY-induced feeding and overfeeding in 24 h fasted rats. These findings demonstrate a role for the Y5, or possibly Y5 in combination with Y1, but not Y2 or Y4 receptor subtypes in feeding. No evidence was found for the existence of an additional, as yet undescribed, NPY feeding receptor.

Animals↗
PubMed1998

The regulatory role of leptin in food intake.

This review discusses recent work that has focused on the interaction of leptin with various neuroendocrine pathways in the brain and in the periphery to affect food intake. Additional consideration is directed towards emerging studies with antibodies and receptor antagonists that show leptin has a physiologically important role in the control of food intake.

Animals↗
PubMed1997

Leptin is a physiologically important regulator of food intake.

OBJECTIVE: These studies were designed to test the hypothesis that endogenous leptin, acting within the brain plays a physiologically important role in the control of food intake in lean rats. DESIGN: Antibodies directed against mouse leptin were raised in rabbits. The purified IgG fractions prepared from pre-immune and immune sera were injected into the right lateral ventricle of lean Sprague-Dawley rats and obese Zucker fatty fa/fa rats. Changes in food intake were measured over the following 20 h period. RESULTS: The anti-leptin antibodies recognized a major epitope in the C-terminal region of the leptin molecule. The antibodies bound both mouse and rat leptin with high affinity, but did not bind human leptin, or a selected range of other hormones and neurotransmitters known to affect food intake. In competition studies, the binding of mouse, but not human leptin to the human Ob-Rb receptor was prevented by the antibodies. This indicates that the antibodies can block the action of leptin by preventing its binding to the ob-Rb receptor. Injection of the anti-leptin antibodies into the brain of lean rats led to an increase in food intake during the first hour after injection which was not compensated during the following 19 h period. Injection of the anti-leptin antibodies did not affect food intake in Zucker fatty fa/fa rats which express an abnormal ob-Rb receptor. CONCLUSION: Endogenous leptin acting within the brain plays a physiologically important role in the control of food intake in lean rats.

Amino Acid Sequence↗
PubMed1997

Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides.

The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subtype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. These conclusions were based on studies with peptidic agonists. We now report studies in which phosphothioate end-protected antisense oligodeoxynucleotides (ODNs) targeted to prepro NPY (prepro NPY antisense ODNs) or to the Y5 receptor (Y5 antisense ODNs) were used to assess the functional importance of this novel receptor subtype in vivo. NPY antisense ODNs given intracerebroventricularly to rats prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasting-induced food intake. Likewise, repeated intracerebroventricular injections of Y5 antisense ODNs prevented fasting-induced food intake in rats. Moreover, two Y5 antisense ODNs, targeted to different sequences of the receptor, significantly decreased basal food intake and inhibited the increase in food intake after intracerebroventricular injection of NPY. These effects proved to be selective, since the feeding response to galanin was not affected. Analysis of the structure of feeding behavior revealed that prepro NPY and Y5 receptor antisense ODNs reduced food intake by inducing decreases in meal size and meal duration analogous to the orexigenic effects of NPY that are mediated by increases in these parameters. Although changes in Y5 receptor density could not be measured, the results with Y5 antisense ODNs strongly suggest that this receptor subtype mediates the feeding response to exogenous and endogenous NPY. Selective Y5 antagonists may therefore be of therapeutic value for the treatment of obesity and eating disorders.

Animals↗
PubMed1992

Alterations in [3H]kainate and N-methyl-D-aspartate-sensitive L-[3H]-glutamate binding in the rat hippocampal formation following fimbria-fornix lesions.

Following lesions of the fimbria-fornix, there is a time-dependent increase in interictal spikes and seizure susceptibility. This may result from sprouting of local excitatory and inhibitory circuits in response to the loss of subcortical and commissural innervation of the hippocampal formation. We used receptor autoradiography to examine the density of N-methyl-D-aspartate (NMDA)-sensitive L-[3H]glutamate and [3H]-kainate (KA) binding sites in the hippocampal formation at 5 days, 3 months, and 1 year following bilateral aspiration lesions of the fimbria-fornix. At 5 days post-lesion, the CA3 and CA1 strata radiatum and oriens displayed a decrease (20-42%, P less than 0.01) in NMDA-sensitive L-[3H]glutamate binding. The initial decrease was followed by a moderate recovery at later time points but was still evident at 1 year postlesion. This may reflect a lesion-induced turnover of synaptic complexes, down-regulation of postsynaptic receptors, or loss of presynaptic receptors. Five days following fimbria-fornix lesion there was also a decrease (13-15%, P less than 0.05) in [3H]KA binding in CA3 strata radiatum and pyramidale. However, at 3 months postlesion KA receptor density was elevated by 29-33% (P less than 0.01) in the outer molecular layer of the dentate gyrus with no significant change in binding to the inner molecular layer. By 1 year postlesion, the density of [3H]KA binding sites was not significantly different from that observed in control animals of the same age. The increase in KA receptor density in the outer molecular layer 3 months after fimbria-fornix lesion may reflect sprouting of the perforant path input or mossy fibers to this region and contribute to the increase in interictal spikes and seizures susceptibility.

Acetylcholinesterase↗
PubMed1988

A homologous in vitro system to analyze transcription of a mouse immunoglobulin mu heavy-chain gene.

In order to investigate the molecular mechanisms of the regulation of immunoglobulin (Ig) gene transcription, a cell-free system was developed in which a cloned mouse Ig mu heavy-chain gene was transcribed using nuclear extracts prepared from a mouse B cell hybridoma line. To monitor transcription, an RNA.RNA hybridization assay was developed in which a 32P-labeled, SP6-synthesized RNA probe complementary to Ig mu RNA was hybridized to unlabeled RNA transcribed in the nuclear extract. Accurate initiation of transcription, which resulted in the protection of the RNA probe from digestion with nuclease S1, was detected by the separation of the products on denaturing polyacrylamide gels, followed by autoradiography. Using this assay, an in-vitro-synthesized RNA was detected. The 5' end of the in-vitro-transcribed Ig mu RNA maps exactly to the same position as the 5' end of the corresponding in vivo mRNA and its formation was sensitive to the addition of low levels of alpha-amanitin (1 microgram/ml), indicating transcription by RNA polymerase II. It was shown by competition experiments with oligonucleotides containing the 'decamer recognition site' that this sequence interacts with (a) decamer-binding factor(s) and plays a positive role in transcription. The competition effects of the decamer-containing oligonucleotide appeared to be restricted to the decamer motif present in the promoter region. No effects of the enhancer region were detectable in vitro. Little or no transcriptional activity was found in transcription experiments using the Ig mu promoter and nuclear extracts prepared from HeLa cells. This suggests that tissue-specific factors involved in Ig mu heavy-chain gene transcription are present in the mouse B cell extracts.

Amanitins↗
PubMed1977

[Correction of tetralogy of Fallot and its influence to oxygen transport and lung changes. Part I. Oxygen transport (author's transl)].

30 patients with tetralogy of Fallot were examined before and after correction. 10 of whom had previous procedures including 13 Blalock-Taussig shunts, 1 Cooley anastomosis and 6 pulmonary valvulotomies (Brock) with a dilator. Hemoglobin and blood gases were measured in 22 patients pre- and postoperatively on the 7th respectively 14th day and finally after 12 months. In 8 children the concentration of 2,3-DPG was accessed (pre-, postoperatively, immediately in ICU, on the 1st, 7th, 14th day and after 21 months). Hypoxia of various degrees was found at any time of the investigation, verified by a low venous oxygen saturation, high 2,3-DPG concentration and an erythrocytosis. The 2,3-DPG concentration was always elevated (preoperatively 18.2 +/- 1.8 muMol/g Hb; postoperatively 1st till 14th day 19.0 +/- 2.2; after 21 months 16.3 +/- 1.2 muMol/g Hb). Preoperatively hypoxia was correlated to the degree of the heart disease expressed by the hight of the Hb-concentration. In contrary after the correction signs of hypoxia (decreased venous oxygen saturation, increased 2,3 DPG-concentration) appeared with a low Hb as found in patients with anemia. The long term check-ups are indicative for slight cardiac residual disorders as there are hypoxic myocardial damage, residual gradients over the right ventricular outlet, reopened VSD's, and ventriculotomy scar tissue. Though the elevated 2,3-DPG-concentration and the consecutive rightward shift of the oxygen saturation curve obviously compensate these cardiac handi-caps as the excellent physical condition of the children shows.

Adolescent↗
PubMed1977

[Correction of tetralogy of Fallot and its influence to oxygen transport and lung changes. Part II: Lung changes (author's transl)].

22 children got lung scans 3 weeks respectively 12 months after the correction of a tetralogy of Fallot. In 18 cases previous operations were done: 12 times a Blalock-Taussig shunt and 6 times a Brock procedure. For the scan 20-70 mu diameter albumin macrospheres were used, which were labeled with Technetium 99m. The following pathologicla lung changes were seen: 1. Loss of perfusion, typical after Blalock-Taussig shunt procedure; these findings were always on the left side, the site of the anastomosis. 2. Anomalous flow distrubution (=more spheres in the upper than in the lower lobe) in the left lung; these changes were also caused by the Blalock-Taussing shunts, but disappeared within the one year follow-up after the correction. 3. Intrapulmonary rigt-left shunts (according to the dilatation of the alveolar capillaries). These decreased within one year from 9.9+/-1.3 to 4.6+/-0.9%.

Adolescent↗