[Neuropeptide Y and serum cholesterol].
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Adipose Tissue↗
Biomedical subjects
U Pesonen
Publications and source records attributed to U Pesonen.
Effects of ZD7114, a selective beta3-adrenoceptor agonist, on neuroendocrine mechanisms controlling energy balance.
Selective beta3-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The aim of this study was to investigate how changes in energy balance affect energy intake and interaction of peripheral metabolic feedback signals with central neuroendocrine mechanisms participating in the control of body energy balance. Expression of preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus and preprocorticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus were measured by in situ hybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl)phenoxyacetamide, 3 mg kg(-1) day(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expression of leptin mRNA in epididymal fat and serum levels of leptin were analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. Treatment with ZD7114 significantly reduced weight gain and activated brown adipose tissue thermogenesis, but had no effect on food intake. Expressions of preproNPY or preproCRF mRNAs were similarly not changed by treatment with ZD7114. Furthermore, ZD7114 had no effect on plasma insulin or leptin and the expression of leptin mRNA in epididymal fat. However, statistically significant correlations were found between preproNPY and preproCRF mRNA expressions and brown fat thermogenic activity and plasma insulin levels in the ZD7114 treated rats, but not in the control rats. It is concluded that treatment with ZD7114 markedly activated brown fat thermogenesis, but did not affect neuropeptide Y (NPY) and CRF gene expression per se. However, the correlation analyses suggest that ZD7114 may modulate feedback connections of brown adipose tissue thermogenesis and plasma insulin with the hypothalamic neuroendocrine mechanisms integrating body energy balance.
Adipose Tissue, Brown↗
Mutation screening of the 5-hydroxytryptamine7 receptor gene among Finnish alcoholics and controls.
Impaired central serotonin neurotransmission has been associated with increased aggression, impaired impulse control and diurnal activity rhythm disturbances among humans. Neuroanatomic distribution and pharmacological properties of the serotonin 5-HT7 receptor suggest that it may play a role in psychiatric disorders and in circadian rhythm regulation. In this study a point mutation causing proline279 --> leucine amino acid substitution in the 5-hydroxytryptamine7 (5-HT7) receptor gene was discovered. This 5-HT7Leu279 variant was observed in six of 825 individuals, all of whom are heterozygous for the substitution. Three of them are alcoholic offenders (3/255), two are relatives of an offender without the 5-HT7Leu279 allele (2/255) and one is a healthy control without any psychiatric diagnosis (1/248). The allele frequency of the 5-HT7Leu279 variant is 0.004 (6/758) among Finns. Although the 5-HT7Leu279 variant is approximately three times more common among alcoholic offenders than among healthy controls, it is not significantly associated with alcoholism or impulsivity in the present study. The 5-HT7Leu279 allele may, however, be a predisposing allele in a subgroup of alcoholic offenders with multiple behavioral problems.
Adult↗
Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels.
High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.
Adult↗
Inverse correlation between serum testosterone and leptin in men.
Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P < 0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.
Adult↗
Identification of new sequence variants in the leptin gene.
The leptin gene (LEP) has been linked to extreme obesity. However, no common obesity-related gene variants have been found to exist in the LEP. The present study was designed to investigate the LEP for variants by screening both the putative promoter and the coding region of this gene in obese Finnish subjects (n = 200; body mass index, > 27 kg/m2). PCR-amplified DNA samples were subjected to single strand conformation analysis. A G144A substitution in codon 48 and a G328A substitution in codon 110 were identified in two obese subjects, both of whom had very low serum leptin levels. A rare silent C538T polymorphism was detected 33 bp downstream of the translation stop codon (TGA). A common polymorphism A19G was identified in the untranslated exon 1. This polymorphism was not associated with traits of obesity; in agreement, the allele frequencies were similar between 64 normal weight and 141 obese Finns. In summary, this study failed to find a common gene variant in the LEP associated with obesity, but introduces 2 rare mutations associated with very low serum leptin concentrations in 2 obese subjects.
Adult↗
Neuropeptide Y: a novel link between the neuroendocrine system and cholesterol metabolism.
High serum total and low-density lipoprotein (LDL) cholesterol levels constitute the main risk factor for atherosclerotic vascular diseases. Both genetic and environmental factors are involved in the regulation of serum cholesterol levels. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, is known to regulate food intake and energy balance but its role in cholesterol metabolism has remained almost untouched in former literature. A newly discovered association between a leucine(7)-to-proline(7) polymorphism (Pro(7)) in the signal peptide of NPY and a high cholesterol level may provide new ideas for the genetic regulation of cholesterol metabolism. The presence of the Pro(7) in NPY results in serum total cholesterol levels 0.6-1.4 mmol/L higher compared with subjects without this gene variant. The Pro(7) in NPY was detected in 14% of Finns but only in 6% of Dutchmen, and its impact on serum cholesterol concentration seems to be stronger in obese than in normal-weight subjects. At least among Finns, the Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol levels.
Arteriosclerosis↗
Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity.
MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.
Adipose Tissue, Brown↗
Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls.
We screened the 5-HT2A receptor gene coding region in 50 patients with seasonal affective disorder (SAD) using a single strand conformational polymorphism analysis and estimated the frequencies of two synonymous and two non-synonymous substitutions we detected in 70 Centre d'Etude du Polymorphism Humain (CEPH) population controls and 62 normal controls. Both of the amino acid substitutions: Ala447-Val447 and His452-Tyr452, were located within the cytoplasmic. C-terminal tail of the receptor. Rarer allele frequencies in CEPH were 0.7% and 9.3% for Val447 and Tyr452, respectively. Allele frequencies of all four polymorphisms, including the two amino acid substitutions, were not significantly different in SAD patients as compared to CEPH and normal controls. Lack of association of Val447 and Tyr452 to SAD is consistent with observations showing normal 5-HT2A receptor Ca2+ response in platelets with this disorder, however, the two 5-HT2A amino acid substitutions may lead to differences in behavioral phenotypes.
Alleles↗
Anorectic effect of metformin in obese Zucker rats: lack of evidence for the involvement of neuropeptide Y.
The hypothalamic neuropeptide Y content and preproneuropeptide Y mRNA expression were studied in metformin-treated (300 mg/kg orally for 12 days), in pair-fed and in ad libitum-fed obese Zucker rats in order to elucidate possible mechanisms involved in the anorectic and body weight reducing effect of chronic metformin treatment in genetically obese Zucker rats. In addition the acute influence of metformin on food intake was studied by comparing its effects after oral and parenteral administration. The concentration of neuropeptide Y in the hypothalamic paraventricular nucleus was significantly higher in the metformin-treated and pair-fed rats when compared to the control animals. The expression of preproneuropeptide Y mRNA in the arcuate nucleus was similar in all three treatment groups. Both chronic metformin treatment and pair-feeding markedly lowered hyperinsulinaemia in these animals. A single subcutaneous dose of metformin (300 mg/kg) reduced food intake only in obese animals, while the same dose of metformin given orally did not affect food intake in either lean or obese animals. It is concluded that the treatment with metformin and pair-feeding, which results in comparable reductions in food intake, body weight gain and hyperinsulinaemia, similarly increase neuropeptide Y concentrations in the paraventricular nucleus while not affecting preproneuropeptide Y mRNA expression in the arcuate nucleus. The increase in hypothalamic neuropeptide Y content may be secondary to the reduction in hyperinsulinaemia during metformin treatment and pair-feeding. Thus, the anorectic effect of chronic metformin treatment cannot be explained by changes in content or expression of hypothalamic neuropeptide Y.
Administration, Oral↗
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↗
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↗
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↗
[Brain neurochemical systems which control appetite].
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Animals↗
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↗
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↗
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↗
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↗