RESUMO
Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.
Assuntos
Anorexia/genética , Peso Corporal , Encéfalo/metabolismo , Neuropeptídeos/genética , Animais , Composição Corporal , Calorimetria Indireta , Ingestão de Alimentos , Metabolismo Energético , Engenharia Genética , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase , Hibridização In Situ/métodos , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Transgênicos , Neuropeptídeos/metabolismo , Reação em Cadeia da Polimerase/métodosRESUMO
The neuropeptide galanin mediates a diverse array of physiological functions through activation of specific receptors. Roles of the three recently cloned galanin receptors (GalRs) in rat intestinal contraction and food intake were examined using GalR-selective ligands and the results were compared with the pharmacological profiles of defined GalRs. The action profile of these ligands in jejunal contraction resembled only that of GalR2 and only a high level of GalR2 mRNA was detected in the tissue, supporting GalR2 as the receptor mediating jejunal contraction. The action profile for food intake in rats excluded GalR2, GalR3 and the putative pituitary galanin receptor as the 'feeding receptor', suggesting that either GalR1 or an unidentified GalR is responsible for mediating this function.
Assuntos
Comportamento Alimentar/fisiologia , Galanina/fisiologia , Jejuno/fisiologia , Receptores de Neuropeptídeos/fisiologia , Animais , Células CHO , Cricetinae , Radioisótopos do Iodo , Masculino , Contração Muscular/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Galanina , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/classificação , Proteínas Recombinantes/metabolismo , SuínosRESUMO
The in vitro metabolism of phencyclidine (PCP) was investigated in 9000 g supernatant fractions of both control and PCP-, ketamine-, ethanol-, phenobarbital- or isosafrole-pretreated rats. Levels of PCP, trans-4-phenyl-4-piperidinocyclohexanol (I), 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (II), N-(5-hydroxypentyl)-1-phenylcyclohexylamine (IX), and 5-(1-phenylcyclohexylamino)-valeric acid (X) were monitored by gas chromatographic analysis in all cases. The inhibition of metabolism by N2, CO, SKF-525A or 2,4-dichloro-6-phenylphenoxyethylamine (DPEA), or deletion of NADPH or protein, implied the involvement of cytochrome P-450 in the reactions. The various inducing agents affected the metabolism of PCP in different ways, implying that at least several isozymes of cytochrome P-450 were involved in the total metabolism. The majority of the consumed PCP was not accounted for by the measured metabolites so that some other metabolic pathways of major quantitative importance must be operative.
Assuntos
Dioxóis/farmacologia , Etanol/farmacologia , Ketamina/farmacologia , Fenciclidina/metabolismo , Fenobarbital/farmacologia , Safrol/farmacologia , Animais , Sistema Enzimático do Citocromo P-450/análise , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Fenciclidina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The present experiment was planned to provide information about relations between behaviorally augmented tolerance and accompanying upregulation of muscarinic receptors (mAChR) (physiological tolerance) in the CNS during chronic administration of the cholinergic antagonist scopolamine. Analyses of the data on mAChR binding established significant upregulation (Bmax) had occurred in the cortex, hippocampus, and striatum of animals treated with scopolamine, but not of those in the saline or methylscopolamine groups. There were no treatment effects in affinity (KD). The effect of scopolamine administered before a behavioral test session was to cause an acute decrease in FR5 responding to water reinforcement, and hence in resulting water consumption. Animals immediately compensated for this decrement by higher response rates during a free drinking (FDR) period which followed. When scopolamine was injected between the FR5 and FDR periods, FR5 responding increased to compensate for the drug's effect on the FDR. There was evidence that physiological tolerance also occurred as indicated by a more slowly developing trend toward recovery of levels of behavioral responding related to mAChR upregulation, although full recovery to pretreatment baselines did not occur within the 25 days of chronic treatments. The results as a whole are consistent with a multifactorial model of tolerance development, to which both behavioral and neurochemical processes contribute.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Tolerância a Medicamentos , Masculino , Quinuclidinil Benzilato , Ratos , Ratos Endogâmicos , Receptores Colinérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Esquema de Reforço , Fatores de TempoRESUMO
Intracerebroventricular (i.c.v.) administration of glucagon-like peptide-1-(7-37) amide (GLP-1) has been shown to modulate food and water intake. The present studies further characterize the effects of i.c.v. GLP-1 in the regulation of energy balance in lean and obese animals. In both obese and lean Zucker rats, a single i.c.v. infusion of GLP-1 (1-30 microg) resulted in a dose-dependent reduction of food intake and decrease in respiratory quotient relative to the saline control during the first 2 h of the nocturnal cycle. In obese Zucker rats, the food intake was reduced by 73 +/- 11% of the control at the 30 microg dose, whereas a modest 45 +/- 18% reduction was observed in lean rats. Despite the large reduction in food intake seen with GLP-1, there was no compensatory decrease in nocturnal oxygen consumption in the obese Zucker rats. Interestingly, low doses of GLP-1 (1 microg) in lean Zucker rats, which had minimal effects on food intake, caused a 19 +/- 7% increase in O2 consumption during the first 2 h of the nocturnal cycle. These data suggest that central GLP-1 may be an important factor controlling negative energy balance in both the lean and obese Zucker rats.
Assuntos
Comportamento de Ingestão de Líquido/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Glucagon/farmacologia , Obesidade/genética , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Análise de Variância , Animais , Peptídeo 1 Semelhante ao Glucagon , Injeções Intraventriculares , Masculino , Ratos , Ratos ZuckerRESUMO
The neuropeptide Y (NPY) Y(5) receptor has been proposed to mediate several physiological effects of NPY, including the potent orexigenic activity of the peptide. However, the lack of selective NPY Y(5) receptor ligands limits the characterization of the physiological roles of this receptor. Screening of several analogs of NPY revealed that [D-Trp(34)]NPY is a potent and selective NPY Y(5) receptor agonist. Unlike the prototype selective NPY Y(5) receptor agonist [D-Trp(32)]NPY, [D-Trp(34)]NPY markedly increases food intake in rats, an effect that is blocked by the selective NPY Y(5) receptor antagonist CGP 71683A. These data demonstrate that [D-Trp(34)]NPY is a useful tool for studies aimed at determining the physiological roles of the NPY Y(5) receptor.
Assuntos
Ingestão de Energia/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Animais , Ligação Competitiva , Células CHO , Linhagem Celular , Cricetinae , AMP Cíclico/metabolismo , Humanos , Cinética , Masculino , Naftalenos/farmacologia , Neuropeptídeo Y/análogos & derivados , Pirimidinas/farmacologia , Ratos , Ratos Long-Evans , Receptores de Neuropeptídeo Y/metabolismo , Proteínas Recombinantes/agonistas , TransfecçãoRESUMO
Upon stretch in normal physiological salt solution (PSS), two dihydropyridine (DHP) Ca2+ agonists (Bay k 8644 and CGP 28392) enhanced the level of stretch-dependent myogenic tone in rabbit ear resistance arteries. This potentiating effect was not blocked by phenoxybenzamine (1 microM) and was Ca2+-dependent. Bay k 8644 was more potent than CGP 28392. These agonists had a smaller potentiating effect on K+ (20 mM)-induced contraction, and had little effect in the presence of high K+ (50-134 mM) PSS. Stretch-dependent myogenic tone is resistant to the inhibitory effect of nimodipine, a selective DHP Ca2+ antagonist which inhibited K+ (50 mM)-induced contraction in the nanomolar range. The potentiating effects of Bay k 8644 and CGP 28392 on myogenic tone were reversed by nimodipine. Our data suggest that DHP Ca2+ agonists selectively enhance myogenic tone by a mechanism that is antagonized by nimodipine, although physiological activation of myogenic tone is nimodipine insensitive, and the calcium related mechanisms of myogenic tone are distinct from those for high K+ depolarization-induced tone.
Assuntos
Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Artérias/efeitos dos fármacos , Cálcio/metabolismo , Técnicas In Vitro , Canais Iônicos/efeitos dos fármacos , Masculino , Nimodipina/farmacologia , Potássio/farmacologia , CoelhosRESUMO
After stretch, tone develops in ring segments of rabbit ear resistance arteries (75-150 micron unstretched lumen diam). This is myogenic tone, since it is not dependent on the presence of sympathetic nerves, endothelial cells, or the local release of any known vasoactive autacoids. It is sensitive to the extracellular Ca2+ concentration, and disappears in a low Ca2+ (25 microM) environment. Tone is restored immediately on the reintroduction of Ca2+ (0.1-1.6 mM). High K+-induced tone in these resistance arteries is also extracellular Ca2+-dependent. The Ca2+ ED50 of this tone is 2.45 X 10(-4) M, which is significantly lower than that for myogenic tone (Ca2+ ED50; 8.31 X 10(-4) M). Both tone moieties are influenced by inorganic Ca2+ antagonists (Mn2+ and Mg2+) and some organic Ca2+ antagonists (verapamil and diltiazem). Among all the Ca2+ antagonists studied, only Mn2+ completely inhibits myogenic tone. In contrast, myogenic tone is resistant to nimodipine (up to 10(-6) M), the most potent Ca2+ antagonist of K+-induced contraction (ID50; 1.0 X 10(-9) M). Other 1,4-dihydropyridine Ca2+ antagonists such as nifedipine and (-)-PN 200-110 selectively antagonize K+-induced contractions, whereas they do not affect the development and the maintenance of myogenic tone. The fact that the (+)-enantiomer of PN 200-110 does not have an inhibitory effect proves that the 1,4-DHP site is stereospecific. These results indicate that extracellular Ca2+ is essential for both stretch-dependent (myogenic) and K+-induced tone, and the Ca2+ entry pathways for the two tone moieties are differently influenced by dihydropyridines.
Assuntos
Artérias/efeitos dos fármacos , Cálcio/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Ácidos Nicotínicos/farmacologia , Análise de Variância , Animais , Diltiazem/farmacologia , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Isradipino , Masculino , Manganês/farmacologia , Nimodipina , Oxidiazóis/farmacologia , Potássio/farmacologia , Coelhos , Resistência Vascular , Verapamil/farmacologiaRESUMO
Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.
Assuntos
Orelha/irrigação sanguínea , Tono Muscular , Resistência Vascular , Animais , Artérias/fisiologia , Masculino , Contração Muscular , Estimulação Física , Coelhos , SimpatectomiaRESUMO
The relative contributions of nitric oxide (NO) to in vitro relaxation responses elicited by acetylcholine (ACh) were compared in vessels of different sizes from the rat mesenteric vascular bed. ACh elicited an endothelium-dependent relaxation in phenylephrine-contracted superior mesenteric arteries (SMA, unstretched luminal diam 650 microns), which was blocked by compounds that inhibited NO, such as hemoglobin (10 microM), methylene blue (10 microM), and NG-monomethyl-L-arginine (1 mM). In contrast, the endothelium-dependent relaxation induced by ACh in phenylephrine-contracted mesenteric resistance arteries (MRA, unstretched luminal diam 200 microns) was not blocked by hemoglobin, methylene blue, or NG-monomethyl-L-arginine. KCl (25 mM) partially inhibited the ACh-dependent relaxation in MRA. Furthermore, the ACh-dependent relaxation in MRA was selectively inhibited by the Ca(2+)-activated K+ channel blocker charybdotoxin (0.1 microM). In contrast, the ATP-sensitive K+ channel blocker glibenclamide (50 microM) did not block the ACh-dependent relaxation in MRA. We conclude that 1) NO is a major component of the ACh-dependent relaxation in SMA and 2) the ACh-dependent relaxation of MRA is resistant to NO inhibitors but sensitive to a Ca(2+)-activated K+ channel blocker. This suggests that an endothelium-derived hyperpolarization factor may be involved in the relaxation of MRA.
Assuntos
Acetilcolina/farmacologia , Circulação Esplâncnica , Vasodilatação , Animais , Artérias , Endotélio Vascular/fisiologia , Masculino , Nitroprussiato/farmacologia , Bloqueadores dos Canais de Potássio , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Circulação Esplâncnica/efeitos dos fármacos , Resistência VascularRESUMO
Melanocortins play a critical role in appetite and body weight regulation, because manipulations of this pathway can lead to the development of obesity in several animal models. The purpose of this study was to use a melanocortin receptor agonist and antagonist to evaluate the involvement of melanocortins in feeding, energy metabolism, and body weight regulation in lean and obese Zucker rats. Central administration of a melanocortin receptor antagonist (SHU9119) elevated food intake and body weight of lean Zucker rats but had little effect in obese Zucker rats. In contrast, the melanocortin receptor agonist MTII reduced food intake in both lean and obese rats but was more potent in the obese Zucker rats. These data indicate the existence of functional melanocortin receptors in both lean and obese Zucker rats but suggest that obese Zucker rats have reduced endogenous melanocortin tone. In addition to its effects on food intake, MTII infusion elevated oxygen consumption and decreased respiratory quotient dose dependently during the light cycle. Our data suggest that a melanocortin receptor agonist can induce weight loss by increasing energy expenditure and promoting body fat utilization in addition to its inhibitory effects on food intake in both obese and lean Zucker rats.
Assuntos
Ingestão de Energia , Metabolismo Energético , Hormônios Estimuladores de Melanócitos/metabolismo , Obesidade/fisiopatologia , Receptores da Corticotropina/metabolismo , Animais , Peso Corporal , Ingestão de Alimentos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Masculino , Hormônios Estimuladores de Melanócitos/farmacologia , Atividade Motora/efeitos dos fármacos , Oxigênio/metabolismo , Ratos , Ratos Zucker , Receptores da Corticotropina/agonistas , Receptores da Corticotropina/antagonistas & inibidores , Receptores de Melanocortina , alfa-MSH/análogos & derivados , alfa-MSH/farmacologiaRESUMO
Genetically obese (ob/ob) mice display a number of metabolic alterations, including decreased thermogenesis, hyperphagia, hyperglycemia and increased body fat. A single intracerebroventricular (i.c.v.) injection of these mice with leptin (0.01 to 1 microg) lowered food intake and body weight within 24 h. In addition, i.c.v. administration of leptin increased 22 h energy expenditure while reducing the respiratory quotient (RQ) in a dose-dependent manner. The leptin-induced decrease in RQ suggests a reduction in the fraction of total energy derived from carbohydrate oxidation and a corresponding increase in energy derived from fat oxidation. Our data suggest that leptin controls energy homeostasis through activation of receptor(s) in the central nervous system (CNS) that regulate both food intake and energy metabolism.
Assuntos
Tecido Adiposo/metabolismo , Regulação da Temperatura Corporal/efeitos dos fármacos , Obesidade/metabolismo , Proteínas/administração & dosagem , Animais , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Injeções Intraventriculares , Leptina , Camundongos , Camundongos Obesos , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagemRESUMO
The thrombin receptor was the first cloned G protein-coupled receptor reported to be activated by proteolytic cleavage of its extracellular amino terminus. A second proteinase-activated receptor (PAR-2) was cloned recently and expressed in Xenopus laevis oocytes. PAR-2 was activated by trypsin and by a peptide (SLIGRL) derived from the new amino terminus. Since PAR-2 mRNA was detected in highly vascularized organs, we compared the physiological functions of the thrombin receptor and PAR-2 in vascular endothelium. Thrombin and trypsin both elicited endothelium-dependent relaxations in prostaglandin F2alpha (PGF2alpha)-contracted strips of porcine coronary artery. Whereas high doses of both thrombin or trypsin (10 U/mL) caused homologous desensitization, trypsin caused further relaxation of thrombin-desensitized tissues. Thrombin and PAR-2-derived peptides (SFLLRN and SLIGRL) both induced endothelium-dependent relaxations in PGF2alpha-contracted porcine coronary arteries. SFLLRN or SLIGRL (30 micronmol/L) also showed homologous desensitization but not cross desensitization. In the presence of the NO synthase inhibitor NG-monomethyl-L-arginine (1 mmol/L), both SFLLRN- and SLIGRL-induced relaxations were partially inhibited. SFLLRN elicited weak contraction in coronary arteries without endothelium, whereas SLIGRL had no effect. Intravenous injection of SFLLRN (1 mg/kg, bolus) into anesthetized rats elicited a transient depressor response followed by pronounced pressor response. In contrast, intravenous administration of SLIGRL (1 mg/kg, bolus) produced only a marked depressor response. Consistent with the in vivo data, SFLLRN contracted the endothelium-rubbed rat aortic rings and aggregated human platelets in vitro, whereas SLIGRL had no effect. The finding that both trypsin and SLIGRL induced endothelium-dependent relaxations indicates the presence of PAR-2 on endothelial cells. In addition, both trypsin and SLIGRL elicited relaxations in thrombin- or SFLLRN-desensitized tissue, suggesting that PAR-2 is distinct from thrombin receptor in vascular endothelium. The lack of PAR-2-mediated platelet aggregation or smooth muscle contraction suggested it might not share the pathogenic properties associated with the thrombin receptor in the vasculature.
Assuntos
Endopeptidases/fisiologia , Endotélio Vascular/química , Receptores de Superfície Celular/fisiologia , Receptores de Trombina/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor PAR-2 , Receptores de Superfície Celular/química , Suínos , Trombina/farmacologia , Tripsina/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
Inbred strains of mice exhibit large genetic variations in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. A tissue-specific genetic variation between the strains BALB/c and C57BL/6, resulting in about 5-fold higher levels in hepatic reductase activity in strain C57BL/6, was examined in detail. The activity difference between these two strains could be explained entirely by differences in hepatic reductase mRNA levels. In genetic crosses, the variation segregated as a single major Mendelian element. Surprisingly, the mode of inheritance was recessive since F1 mice exhibited the BALB/c levels of enzyme activity. Despite the fact that the rates of hepatic sterol synthesis also differed between the strains by a factor of about five, the altered hepatic reductase expression did not significantly influence plasma lipoprotein levels. The response to a high cholesterol, high fat diet between the strains was remarkably different. Thus, in BALB/c mice, both hepatic reductase activity and mRNA levels were affected only slightly, if at all, by cholesterol feeding, while in strain C57BL/6 mice both were reduced more than 10-fold by cholesterol feeding. Several lines of evidence, including analysis of cis-acting regulatory elements, the nonadditive mode of inheritance, and genetic studies of the HMG-CoA reductase gene locus on mouse chromosome 13, support the possibility that the variation in reductase expression is not due to a mutation of the structural gene but, rather, is determined by a trans-acting factor controlling reductase mRNA levels. The variation provides a striking example, at the molecular level, of the importance of dietary-genetic interactions in the control of cholesterol metabolism.
Assuntos
Colesterol na Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Regulação Enzimológica da Expressão Gênica , Hidroximetilglutaril-CoA Redutases/genética , Fígado/enzimologia , Animais , Sequência de Bases , Colesterol/sangue , Resina de Colestiramina/farmacologia , Ritmo Circadiano , Feminino , Variação Genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Hidroximetilglutaril-CoA-Redutases NADP-Dependentes , Lipídeos/sangue , Lovastatina/farmacologia , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Especificidade de Órgãos , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Obesity occurs whenever energy intake exceeds energy expenditure. The ob gene product leptin is a potent anorectic agent when administered to ob/ob mice, but its effects on energy expenditure have not been investigated in detail. The present study was designed to analyze the acute metabolic effects of leptin in vivo. Analysis of oxygen consumption in ob/ob mice demonstrated a reduction in energy expenditure compared with lean controls; this reduction showed a diurnal fluctuation and was most evident during the light cycle. A single intraperitoneal dose of leptin increased oxygen consumption during the light cycle in ob/ob mice, ablating the circadian fluctuation in this parameter. In addition, leptin had a profound effect on fuel selection: the respiratory quotient was markedly reduced, indicating a reduction in carbohydrate oxidation and an increase in fat oxidation. These acute effects of leptin on metabolic parameters are consistent with the selective loss of body fat observed on chronic leptin treatment and suggest that increased energy utilization plays an important role in the anti-obese actions of leptin.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Metabolismo dos Lipídeos , Obesidade/metabolismo , Proteínas/farmacologia , Análise de Variância , Animais , Calorimetria Indireta , Ritmo Circadiano/efeitos dos fármacos , Clonagem Molecular , Escuridão , Escherichia coli , Humanos , Leptina , Luz , Camundongos , Camundongos Obesos , Obesidade/genética , Consumo de Oxigênio , Proteínas Recombinantes/farmacologia , Magreza , Fatores de TempoRESUMO
Intracerebroventricular (ICV) administration of neuropeptide Y (NPY) has been shown to decrease energy expenditure, induce hypothermia, and stimulate food intake. Recent evidence has suggested that the Y5 receptor may be a significant mediator of NPY-stimulated feeding. The present study attempts to further characterize the role of NPY Y5-receptor subtypes in feeding and energy expenditure regulation. Satiated Long-Evans rats with temperature transponders implanted in the interscapular brown adipose tissue (BAT) displayed a dose-dependent decrease in BAT temperature and an increase in food intake after ICV infusion of NPY. Similar effects were induced by ICV administration of peptide analogs of NPY that activate the Y5 receptor, but not by analogs that activate Y1, Y2, or Y4 receptors. Furthermore, ICV infusion of the Y5 selective agonist D-[Trp(32)]-NPY significantly reduced oxygen consumption and energy expenditure of rats as measured by indirect calorimetry. These data suggest that the NPY Y5-receptor subtype not only mediates the feeding response of NPY but also contributes to brown fat temperature and energy expenditure regulation.