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M Koulu

Publications and source records attributed to M Koulu.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of metformin treatment on glucose transporter proteins in subcellular fractions of skeletal muscle in (fa/fa) Zucker rats.

1. The present study was designed to clarify the cellular mechanism through which the antihyperglycaemic drug, metformin, exerts its effects. For this purpose the contents of glucose transporter protein isoforms GLUT1 and GLUT4 were measured in plasma membrane and intracellular membrane fractions of skeletal muscle obtained from genetically obese, insulin-resistant Zucker rats. 2. Hindlimb muscles were dissected from metformin-treated (300 mg kg-1 day-1, p.o., for 12 days) and control rats in basal treatment state, and after acute stimulation with insulin (22 u kg-1, i.p.). Since metformin treatment reduces food intake, we also used a pair-fed control group to investigate the effects of altered insulinaemia per se. Glucose transporter levels were analysed by Western blot and slot blot-techniques. In addition, 2-deoxy-[14C]-glucose uptake in isolated muscle strips was evaluated. 3. No changes were noted in the contents of GLUT1 proteins in any of the subcellular fractions after metformin treatment. The contents of GLUT4 in subcellular fractions were not altered in the basal treatment state. After acute insulin exposure the content of GLUT4 in the intracellular membrane fraction declined significantly in the metformin-treated group, while no significant effect was seen in the plasma membrane fraction. In agreement with these results, metformin treatment did not alter 2-deoxyglucose uptake into isolated muscle strips. 4. In conclusion, the present study does not support the concept that metformin would enhance translocation of glucose transporter proteins from the intracellular compartment to the plasma membrane in skeletal muscle in vivo.

Animals↗
PubMed1994

Hepatic metabolism and distribution of mifepristone and its metabolites in rats.

The hepatic metabolism of mifepristone was studied in female Wistar rats following oral administration of 10 mg/kg. The extraction of mifepristone by the rat liver was effective, eliminating 80% of the mifepristone. During the absorption phase, the portal serum concentrations of mifepristone were over 10-fold higher than those measured in systemic serum. The serum concentrations of the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone were lower in systemic serum, indicating that the metabolites were also effectively excreted by the rat liver. The distribution of mifepristone and its demethylated metabolites between serum, brain, muscle and adipose tissue was studied in lean and obese Zucker rats following repeated oral administration of 10 mg/kg. The individual serum concentrations of mifepristone varied considerably, from 24-482 ng/ml; the mean (+/- SE) serum concentrations for lean and obese rats were 167 (+/- 86) and 211 (+/- 62) ng/ml respectively. Mifepristone could be measured in brain in each animal, its concentrations being 28% of those measured in serum. Muscle tissue and serum contained approximately similar concentrations of mifepristone. Adipose tissue effectively concentrated mifepristone, and its concentrations were 40-fold higher in fat than in serum. The difference in the concentrations of mifepristone between the lean and obese animals was statistically significant only in brain tissue (P < 0.05). The serum concentrations and brain, muscle and adipose tissue concentrations of mifepristone were significantly correlated (P < 0.05). The distribution of the demethylated metabolites was roughly similar to that of mifepristone. However, their concentrations were significantly higher (P < 0.02) in the obese animals in each tissue type investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Potentiation of the anti-obesity effect of the selective beta 3-adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise.

UNLABELLED: 1. The effects of chronic treatments with a selective beta 3-adrenoceptor agonist and a selective alpha 2-adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity. 2. BRL 35135 (beta 3-agonist, 0.5 mg kg-1 day-1 p.o.), atipamezole (alpha 2-antagonist, 4.0 mg kg-1 day-1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise. 3. Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45-fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels. 4. The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135-treated-exercise-trained animals, although neither beta 3-agonist nor exercise alone affected it. 5. Based on the present results in genetically obese Zucker rats, combination of 03-agonist treatment with a moderate physical training may offer a new feasible approach to the therapy of obesity.- KEYWORDS: BRL 35135; atipamezole; P3-adrenoceptor agonism; M2-adrenoceptor antagonism; brown adipose tissue; thermogenesis;genetic obesity; Zucker rat; exercise; neuropeptide Y

Adipose Tissue↗
PubMed1994

COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise.

We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Metformin and brown adipose tissue thermogenetic activity in genetically obese Zucker rats.

The effect of chronic metformin treatment on brown adipose tissue thermogenetic activity was investigated in young genetically obese Zucker rats. The binding of [3H]GDP to brown adipose tissue mitochondria, expression of uncoupling protein mRNA in brown adipose tissue, weight gains and cumulative food intakes were measured in metformin (320 mg/kg orally for 12 days)-treated obese Zucker rats as well as in pair-fed--and in ad libitum--fed control obese rats. The weight gains were identically reduced in the metformin- and pair-fed control group compared to the ad libitum--fed rats. Metformin also significantly reduced cumulative food intake. The binding of [3H]GDP to brown adipose tissue mitochondria and the expression of uncoupling protein mRNA in brown adipose tissue were not modified by metformin. It is concluded that the weight gain reducing effect of metformin in obese Zucker rats is mainly due to reduced food intake and does not involve an effect of metformin on brown adipose tissue thermogenetic activity.

Adipose Tissue, Brown↗
PubMed1993

Effect of chronic treatment with TFMPP, a 5-HT1 receptor agonist, on food intake, weight gain, plasma insulin and neuropeptide mRNA expression in obese Zucker rats.

1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), a 5-HT1 receptor agonist, decreases food intake in rats when given acutely. The present investigation was performed to study the chronic effects of TFMPP on food intake and weight gain in genetically obese Zucker rats. Neurochemical and endocrine data on possible mechanisms involved in the action of TFMPP were collected at the end of the study. TFMPP (4 mg/kg per day s.c.) significantly reduced food intake on the 1st and 7th days, but no longer on the 14th and 28th days. Reduced food intake was associated with decreased body weight gains during the first two weeks of treatment, but no effect was found thereafter. Plasma insulin concentration was significantly lowered by TFMPP treatment without impairment of glucose homeostasis. In situ hybridization analysis did not reveal changes in the expression of preprocorticotropin-releasing factor mRNA in the paraventricular nucleus or preproneuropeptide Y mRNA in the arcuate nucleus. Chronic TFMPP administration significantly reduced the density of 5-HT2 receptors, as measured by quantitative receptor autoradiography, in the claustrum and cerebral cortex, but not 5-HT1C receptor density in the choroid plexus. It is concluded that the anorectic and weight gain-lowering effects of TFMPP decrease during long-term treatment in obese Zucker rats.

Animals↗
PubMed1993

Reduced turnover of dopamine and 5-hydroxytryptamine in discrete dopaminergic, noradrenergic and serotonergic rat brain areas after acutely administered medetomidine, a selective alpha 2-adrenoceptor agonist.

Monoamine metabolism and turnover were investigated in discrete dopaminergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective alpha 2-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 micrograms/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). In a separate experiment, the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) was measured after inhibition of L-aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 micrograms/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5-HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective alpha 2-adrenoceptor blocking agent, on the medetomidine-induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5-HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the alpha 2-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1-C1 area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1-C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1993

Metformin and liver glycogen synthase activity in obese Zucker rats.

The effect of chronic treatment with metformin (320 mg/kg/day) on plasma glucose and insulin as well as liver glycogen synthase activity and hepatic glycogen content was studied in obese hyperinsulinemic Zucker rats. Metformin significantly reduced both plasma glucose (by 10%) and insulin levels (by 39%) at fasting but had no effect on hepatic glycogen content or on the basal activity of liver glycogen synthase.

Animals↗
PubMed1992

Determination of metformin in plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of metformin, an oral antidiabetic agent, in plasma is described. Plasma samples containing the internal standard, phenformin, are eluted through Amprep extraction columns before injection into the chromatographic column, packed with microBondapak phenyl. The eluent is monitored at 236 nm. At a mobile phase flow-rate of 1.35 ml/min, the retention times of metformin and phenformin are 2.8 and 5.6 min, respectively. The intra-day coefficients of variation are 1.5 and 4.3% at metformin concentrations of 0.05 and 1 mg/l, respectively.

Animals↗
PubMed1992

Alpha 2-adrenoceptor density in forebrain areas of Zucker rats: no effect of genetic obesity or antiglucocorticoid treatment.

The density of alpha 2-adrenoceptors was determined in different forebrain regions of lean and obese Zucker rats by para-[125I]iodoclonidine ([125I]PIC) receptor autoradiography. No significant differences were observed between the Zucker phenotypes in the density of alpha 2-adrenoceptors in any brain areas examined. Four days treatment with the antiglucocorticoid mifepristone (RU 38486) did not affect [125I]PIC-binding. It is concluded that the hyperphagia and abnormal corticosterone secretion of genetically obese Zucker rats do not appear to be associated with changes in alpha 2-adrenoceptor density in brain.

Animals↗
PubMed1992

Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats.

The effect of subchronic metformin treatment on food intake, weight gain and plasma and tissue hormone levels was investigated in genetically obese male Zucker rats and in their lean controls. Metformin hydrochloride (320 mg/kg/day for 14 days in the drinking water) significantly reduced 24 hour food intake both after one and two weeks treatment in obese rats. In contrast, metformin had only a transient effect on food intake in lean animals. The reduced food intake was associated with body weight decrease, particularly in obese rats. Metformin markedly reduced also the hyperinsulinemia of the obese animals without altering their plasma glucose or pancreatic insulin content which may reflect an improved insulin sensitivity after metformin treatment. Metformin did not change plasma corticosterone levels or insulin and somatostatin concentrations in the pancreas. Metformin reduced pyloric region somatostatin content in lean rats. It is concluded that metformin has an anorectic effect and reduces body weight and hyperinsulinemia in genetically obese Zucker rat.

Animals↗
PubMed1992

Hypothalamic neuropeptide expression after food restriction in Zucker rats: evidence of persistent neuropeptide Y gene activation.

The Obese Zucker rat is a model of genetic obesity characterized by hyperphagia, hyperinsulinemia and other endocrine abnormalities. In order to elucidate pathogenetic mechanisms contributing to disturbed feeding behavior in these animals, the effect of food restriction on three hypothalamic neuropeptides involved in the control of food intake was studied. Eighteen male obese and 18 lean Zucker rats were randomly divided into two groups: half of the animals were food-restricted for 2 weeks, while the other half served as controls and were fed ad libitum. The levels of preproneuropeptide Y (preproNPY), preprocorticotropin releasing factor (preproCRF) and preprosomatostatin (preproSOM) mRNAs were determined using in situ hybridization technique. In addition, plasma insulin and corticosterone concentrations were analyzed. Food restriction significantly increased the expression of preproNPY mRNA in the arcuate nucleus in both Zucker phenotypes, while the expressions of preproCRF mRNA in the paraventricular nucleus (PVN) and preproSOM mRNA in the periventricular nucleus (PeV) were not altered. The expression of preproNPY mRNA was significantly greater in control obese animals compared to control lean animals. Food restriction lowered plasma insulin levels, but did not change plasma corticosterone levels. It is concluded that food restriction specifically activates NPY gene transcription in the arcuate nucleus the response being similar in both Zucker phenotypes. The results suggest that orexigenic NPY plays a role in the adaptation to altered feeding status.

Animals↗
PubMed1992

Chronic clozapine treatment down-regulates serotonin 5-HT-1c receptors in rat brain.

1. The effects of chronic treatment with the atypical antipsychotic, clozapine, and classical antipsychotic, haloperidol, on serotonergic 5-HT-1c and dopamine D2 receptors in rat brain were studied with radioligand binding methods. 2. Two weeks' treatment with clozapine did not alter striatal D2 receptor characteristics measured with 3H-spiperone, but caused a 54% down-regulation of 3H-mesulergine binding to 5-HT-1c receptors in choroid plexus. 3. In contrast, two weeks' treatment with a classical neuroleptic, haloperidol increased significantly D2 receptor number in striatum, but had no effect on 5-HT-1c receptor binding. 4. In conclusion, alterations of 5-HT-1c receptor characteristics after chronic clozapine treatment may represent a mechanism that contributes to the unique clinical profile of this antipsychotic drug.

Animals↗
PubMed1992

Differential hypothalamic arginine vasopressin response to glucocorticoid receptor antagonism in lean and obese Zucker rats.

The obese Zucker rat (fa/fa) is an animal model for genetic obesity characterized by hyperphagia, hyperinsulinemia, and severe insulin resistance in peripheral tissues. Adrenal steroids seem to play an important role in the onset of fatty syndrome in these animals. There is strong evidence of abnormal regulation of the hypothalamic-pituitary-adrenal axis in obese Zucker rats. Considering the physiological function of arginine vasopressin (AVP) as an adrenocorticotropic hormone secretagogue, the present study was carried out to investigate the role of glucocorticoids in the control of hypothalamic AVP systems in lean and obese Zucker rats. In the first experiment, mifepristone (RU 38486), a glucocorticoid receptor antagonist, was administered for 4 days (10 mg/kg orally twice daily), and the expression of AVP mRNA in hypothalamic paraventricular and supraoptic nuclei was measured using in situ hybridization, and the concentrations of AVP in the pituitary gland and in the median eminence were quantified. Plasma corticosterone levels were also analyzed. Mifepristone treatment resulted in a threefold increase in plasma corticosterone levels in lean Zucker rats, but it did not change corticosterone secretion in obese animals. Mifepristone treatment decreased AVP mRNA levels in lean animals in the supraoptic nuclei, while in obese animals the AVP mRNA content was increased in the paraventricular nuclei. Mifepristone treatment significantly increased the concentration of AVP in the median eminence in lean rats and decreased it in obese animals. Mifepristone treatment did not change concentrations of AVP in the pituitary gland. In the second experiment, mifepristone was given for 4 days (10 mg/kg orally twice daily), and its effects on 24-hour food intake and plasma AVP concentrations were measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The glucocorticoid antagonist mifepristone reveals abnormal regulation of the adrenocortical system in obese Zucker rats.

The effects of the potent glucocorticoid type-II receptor (GR) antagonist, mifepristone, on corticosterone secretion and on expression of preprocorticotrophin-releasing factor (preproCRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and of pro-opiomelanocortin (POMC) mRNA in the pituitary gland were investigated in lean and obese Zucker rats. Treatment with mifepristone for 4 days (10 mg/kg orally twice daily) significantly (P less than 0.05) stimulated corticosterone secretion in lean but not in obese rats. In lean rats the enhanced corticosterone secretion was associated with non-significant increments in the expression of preproCRF mRNA in the PVN and of POMC mRNA in the pituitary gland, while mifepristone significantly (P less than 0.05) reduced the expression of preproCRF mRNA in the PVN of obese Zucker rats. It is concluded that antagonism of GR by mifepristone results in persistent activation of the adrenocortical axis in lean Zucker rats due to blockade of feedback inhibition by circulating corticosterone. In obese animals the abnormal response to mifepristone suggests that the neuroendocrine control of the HPA axis is altered in genetically determined obesity.

Animals↗
PubMed1991

Brain monoamine metabolism and rotational behaviour induced by experimental herpes simplex virus encephalitis.

The motor behaviour and brain concentrations of dopamine, noradrenaline, serotonin and their metabolites have been examined in rabbits with experimental herpes simplex virus (HSV) brain infection achieved by unilateral corneal inoculation. The animals showed altered motor behaviour, consisting of a posture tilting to the side of inoculation and circling in the same direction, that began on day 4-5 post inoculation, and was most vigorous on day 7 post inoculation. Compared with controls, the concentration of 5-hydroxyindoleacetic acid was increased in the caudate nucleus on both sides and that of serotonin was decreased in the nucleus accumbens on the side of inoculation. The circling of the animals correlated positively with the ratio of homovanillic acid concentrations between the left and right caudate nucleus, although the actual concentrations did not differ from the controls. The posture asymmetry correlated with the ratio of the left and right nucleus accumbens homovanillic acid concentrations. The results demonstrate that experimental HSV infection in the brain alters motor behaviour, in association with changes in brain dopamine and serotonin metabolism in the major ascending monoamine systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Effect of a single dose of TCDD on the level of histamine in discrete nuclei in rat brain.

Histaminergic neurones may be involved in the regulation of feed intake. Since TCDD causes anorexia in rats, histamine concentrations were measured in several hypothalamic nuclei involved in feeding regulation. Histamine concentrations were not changed in medial or lateral accumbens, suprachiasmatic, paraventricular, arcuate, ventromedial, dorsomedial or perifornical nuclei, or in lateral hypothalamic area, cortex, or pineal gland. There was, however, an increase in histamine concentration in median eminence 25 h after the administration of TCDD.

Animals↗