RESUMO
AIM: Oxytocin administration to diet-induced obese (DIO) rodents, monkeys and humans decreases body weight and fat mass with concomitant improvements in glucose metabolism. Moreover, several studies show an immunomodulatory role of oxytocin in a number of settings (such as atherosclerosis, injury, sepsis). This study aims to shed some light on the effects of oxytocin on macrophage polarization and cytokine production, as well as its possible impact on these parameters in adipose tissue in DIO mice with impaired glucose metabolism. METHODS: Mouse bone marrow cells were differentiated into macrophages and treated with oxytocin. Macrophage proliferation, cytokine secretion and macrophage populations were determined. For experiments in vivo, DIO mice were treated with oxytocin for 2 weeks. Body weight and composition and glucose tolerance were subsequently followed. At the end of treatment, adipose tissue macrophage populations, plasma cytokine levels and cytokine expression in adipose tissue were determined. RESULTS: In bone marrow-derived macrophages, oxytocin induced an anti-inflammatory phenotype (decreased M1/M2 ratio). In M1-derived macrophages, oxytocin decreased TNFα secretion, with no effects on the other cytokines tested nor any effect on cytokine secretion by M2-derived macrophages. Oxytocin treatment in DIO mice in vivo led to decreased body weight accompanied by an improvement in glucose tolerance, with no changes in plasma cytokine levels. In adipose tissue, oxytocin decreased Tnfα expression without modifying the M1/M2 macrophage ratio. CONCLUSION: Oxytocin treatment decreases TNFα production both in vitro (in bone marrow-derived macrophages) and in vivo (in epididymal adipose tissue) in DIO mice. This effect may also be contributory to the observed improvement in glucose metabolism.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ocitocina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Tecido Adiposo/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Macrófagos/metabolismo , CamundongosRESUMO
BACKGROUND AND PURPOSE: mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti-cancer agents. However, new-onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms associated with the diabetogenic effects of chronic Sirolimus administration in rats and in in vitro cell cultures. EXPERIMENTAL APPROACH: Sirolimus was administered to rats fed either a standard or high-fat diet for 21 days. Metabolic parameters were measured in vivo and in ex vivo tissues. Insulin sensitivity was assessed by glucose tolerance tests and euglycaemic hyperinsulinaemic clamps. Rapamycin effects on glucose metabolism and insulin signalling were further evaluated in cultured myotubes. KEY RESULTS: Sirolimus induced a decrease in food intake and concomitant weight loss. It also induced specific fat mass loss that was independent of changes in food intake. Despite these beneficial effects, Sirolimus-treated rats were glucose intolerant, hyperinsulinaemic and hyperglycaemic, but not hyperlipidaemic. The euglycaemic hyperinsulinaemic clamp measurements showed skeletal muscle is a major site of Sirolimus-induced insulin resistance. At the molecular level, long-term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin-induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane. In rats fed a high-fat diet, these metabolic defects were exacerbated, although Sirolimus-treated animals were protected from diet-induced obesity. CONCLUSIONS AND IMPLICATIONS: Taken together, our data demonstrate that the diabetogenic effect of chronic rapamycin administration is due to an impaired insulin action on glucose metabolism in skeletal muscles.
Assuntos
Imunossupressores/toxicidade , Resistência à Insulina , Sirolimo/toxicidade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Animais , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Glucose/metabolismo , Técnica Clamp de Glucose , Intolerância à Glucose/induzido quimicamente , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Redução de Peso/efeitos dos fármacosRESUMO
AIMS: Ghrelin is one of the most potent orexigens known to date. Recent data suggested that ghrelin is involved in reward-mediated processes such as the rewarding value of food. Whereas the neuronal pathways by which ghrelin regulates energy balance are well described, those involved in ghrelin-induced reward are still confusing. Therefore, we attempted to delineate the involvement of physiological and pharmacological rises in plasma ghrelin in the modulation of food reward seeking behaviours, using the classical conditioned place preference (CPP) procedure in C57BL6J mice, as well as in mice lacking the ghrelin receptor (GHSR1a -/-). We also determined whether these effects on reward-related behaviours could be partly mediated by cholinergic pathways by pre-treating mice with mecamylamine. RESULTS: Upon moderate caloric restriction, systemic ghrelin levels increased from 108 ± 21 to 148 ± 39 pg/ml in C57BL6J mice and from 111 ± 24 to 179 ± 41 pg/ml in GHSR1a-null mice. Short exposure to rewarding food elicited a strong CPP and stimulation of locomotor activity in GHSR1a wild-type and C57BL6J mice. Conversely, the GHSR1a -/- mice did not exhibit such a food CPP, despite a negative energy balance. Pharmacological rise in systemic ghrelin further increased the time spent in the food-paired side with a higher CPP score (+71%) and this effect was blunted after cholinergic blockade by mecamylamine. CONCLUSIONS: The ghrelin receptor is obligatory to acquire a food-CPP. The level of plasma ghrelin during conditioning determines the strength of food-induced reward seeking behaviours. The cholinergic pathway partly mediates the further enhancement of food reward induced by pharmacological rises in plasma ghrelin, but not that induced by physiological increases in ghrelin.
Assuntos
Comportamento de Escolha/fisiologia , Condicionamento Clássico/fisiologia , Grelina/fisiologia , Mecamilamina/farmacologia , Antagonistas Nicotínicos/farmacologia , Recompensa , Animais , Restrição Calórica/métodos , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Grelina/antagonistas & inibidores , Grelina/sangue , Grelina/genética , Grelina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologiaRESUMO
Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity.
Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Glucose/metabolismo , Receptores de Canabinoides/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Antagonistas de Receptores de Canabinoides , Moduladores de Receptores de Canabinoides/antagonistas & inibidores , Moduladores de Receptores de Canabinoides/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Biológicos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Obesidade/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptores de Canabinoides/metabolismo , Rimonabanto , RoedoresRESUMO
OBJECTIVE: To investigate the impact of beta-adrenoceptor deficiency on the metabolic effects of leptin. MEASUREMENTS: Leptin was infused subcutaneously through an osmotic minipump in wild-type (WT) and beta(1)/beta(2)/beta(3)-adrenoceptor knockout (beta-less) mice and its effects on food intake, energy expenditure, carbohydrate and lipid utilization as well as on the levels of expression of the brown adipose tissue (BAT), thermogenic marker uncoupling protein-1 (UCP1) and type II deiodinase (D2) mRNAs were compared. RESULTS: Leptin treatment decreased food intake by 23% in both the WT and the beta-less mice. In pair-fed animals being used as controls, leptin treatment was found to increase energy expenditure in WT, but not in beta-less mice. No difference was observed in carbohydrate or fat utilization between leptin-treated WT and beta-less mice. Leptin increased UCP1 and D2 mRNA levels in WT mouse BAT 1.7- and 3-fold, respectively, but had no effect on the expression of these genes in beta-less mouse BAT. CONCLUSION: The stimulatory effects of leptin on oxygen consumption, BAT UCP1 and D2 expression require functional beta-adrenoceptors, but its inhibitory effect on food intake and its stimulatory effect on fat utilization is independent of the beta-adrenoceptor signalling.
Assuntos
Tecido Adiposo Marrom/metabolismo , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Leptina/farmacologia , Receptores Adrenérgicos beta/deficiência , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Calorimetria Indireta/métodos , Métodos de Alimentação , Iodeto Peroxidase/metabolismo , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Receptores Adrenérgicos beta/fisiologia , Proteína Desacopladora 1 , Iodotironina Desiodinase Tipo IIRESUMO
The metabolic syndrome (MS) describes a cluster of metabolic disturbances including type 2 diabetes and/or insulin resistance, hypertension, dyslipidemia and obesity, which predict a high risk of cardiovascular disorders. The associated hyperinsulinemia and hyperleptinemia may contribute to the cardiovascular risk. However, the operational value of the MS in elderly patients is questionable. We therefore investigated the prevalence and significance of the MS in geriatric care. In a survey of 98 consecutive admissions of diabetic patients, <40% had a MS; this is a low value compared to younger diabetic adults, due to a low prevalence of obesity and dyslipidemia. We found a high prevalence of low BMI (<20 kg/m2), hypoalbuminemia and low total cholesterol levels, suggesting that the MS may be modified by undernutrition. The interplay between the MS and undernutrition was further studied in 30 non-diabetic patients. Both leptinemia and insulin resistance indexes (HOMA-IR and QUICKI) were strongly associated with BMI and body fat (measured by Bioelectrical impedance Analysis). BMI, leptinemia and insulin resistance indexes were associated with the Mini Nutritional Assessment (MNA) score. Thus, undernutrition is associated with low leptin and insulin levels and may obscure the association of these parameters with cardiovascular risk. In conclusion, the MS has a low prevalence in our population of elderly diabetic patients, and is of questionable prognostic value. It can be oveshadowed by undernutrition, which is associated with low body weight, leptinemia and insulin resistance indexes. Prevention of undernutrition and/or adjustment to its consequences should receive higher priority in the care of elderly diabetic patients.
Assuntos
Resistência à Insulina/fisiologia , Insulina/sangue , Leptina/sangue , Desnutrição/diagnóstico , Síndrome Metabólica/diagnóstico , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Hospitais Especializados , Humanos , Inflamação/etiologia , Desnutrição/sangue , Síndrome Metabólica/sangue , Avaliação Nutricional , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents. METHODS: We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents. RESULTS: We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn ( -/- )animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn ( -/- ) animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5 days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake. CONCLUSIONS/INTERPRETATION: The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistance.
Assuntos
Gorduras na Dieta/efeitos adversos , Resistência à Insulina/fisiologia , Insulina/fisiologia , Obesidade/fisiopatologia , Receptores de Interleucina-1/antagonistas & inibidores , Sialoglicoproteínas/fisiologia , Tecido Adiposo/fisiopatologia , Animais , Glicemia/análise , Deleção de Genes , Regulação da Expressão Gênica , Técnica Clamp de Glucose , Insulina/sangue , Resistência à Insulina/genética , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/fisiologia , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Obesidade/etiologia , Obesidade/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/fisiologia , Receptores Tipo II de Interleucina-1 , Sialoglicoproteínas/genética , Sialoglicoproteínas/farmacologia , Transdução de Sinais , Regulação para CimaRESUMO
OBJECTIVES: Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). METHODS: Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4. RESULTS: Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. CONCLUSIONS: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.
Assuntos
Inibidores Enzimáticos/farmacologia , Hipotireoidismo/enzimologia , Iodeto Peroxidase/antagonistas & inibidores , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina Reversa/farmacologia , Animais , Hipotireoidismo/sangue , Iodeto Peroxidase/metabolismo , Masculino , Propiltiouracila , Ratos , Ratos Wistar , Tireotropina/antagonistas & inibidores , Tireotropina/sangue , Tiroxina/sangueRESUMO
AIMS/HYPOTHESIS: The aims of this work were to determine the effect of hypothyroidism on insulin-stimulated glucose turnover and to unravel the potential mechanisms involved in such an effect. METHODS: Hypothyroidism was induced by administration of propylthiouracil, with partial T4 substitution. Euglycaemic-hyperinsulinaemic clamps, associated with the labelled 2-deoxy-D-glucose technique for measuring tissue-specific glucose utilisation, were used. To assess a possible involvement of leptin in the modulation of glucose metabolism by hypothyroidism, leptin was infused intracerebroventricularly for 6 days. A group of leptin-infused rats was treated with rT3 to determine a potential role of T3 in mediating the leptin effects. RESULTS: Compared with euthyroid rats, hypothyroid animals exhibited decreased overall glucose turnover and decreased glucose utilisation indices in skeletal muscle and adipose tissue. Leptinaemia in hypothyroid rats was lower while resistin mRNA expression in adipose tissue was higher than in euthyroid animals. Intracerebroventricular leptin infusion in hypothyroid rats partially restored overall, muscle and adipose tissue insulin-stimulated glucose utilisation and improved the reduced glycaemic response observed during insulin tolerance tests. The leptin effects were due neither to the observed increase in plasma T3 levels nor to changes in the high adipose tissue resistin expression of hypothyroid rats. The administration of leptin to hypothyroid animals was accompanied by increased expression of muscle and adipose tissue carnitine palmitoyl transferases, decreased plasma NEFA levels and reduced muscle triglyceride content. CONCLUSIONS/INTERPRETATION: Hypothyroidism is characterised by decreased insulin responsiveness, partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by intracerebroventricular leptin administration.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Hipertireoidismo/metabolismo , Leptina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos não Esterificados/sangue , Expressão Gênica/genética , Glucose/farmacologia , Técnica Clamp de Glucose , Hormônios Ectópicos/genética , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/genética , Insulina/sangue , Insulina/farmacologia , Resistência à Insulina/fisiologia , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Leptina/administração & dosagem , Leptina/sangue , Masculino , Músculo Esquelético/química , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Propiltiouracila , Ratos , Ratos Wistar , Resistina , Tireotropina/sangue , Tiroxina/sangue , Tiroxina/farmacologia , Triglicerídeos/análise , Triglicerídeos/sangue , Tri-Iodotironina/sangue , Tri-Iodotironina Reversa/farmacologia , Iodotironina Desiodinase Tipo IIRESUMO
Glucocorticoids are important hormones in the regulation of metabolic homeostasis. We infused normal rats with dexamethasone given intracerebroventricularly (i.c.v.) for 3 days. This resulted in hyperphagia, hyperinsulinemia, and marked insulin resistance. Similar metabolic defects were observed following i.c.v. infusion of neuropeptide Y (NPY) in normal rats. As central dexamethasone infusion enhanced NPY content in the arcuate nucleus, it suggested that its metabolic effects are mediated by NPY. Moreover, due to the lack of effects observed in vagotomized animals, activation of the parasympathetic nervous system by central dexamethasone infusion is proposed. Glucocorticoid action is known to involve prereceptor metabolism by enzymes such as 11beta-HSD-1 that converts inactive into active glucocorticoids. Mice overexpressing 11beta-HSD-1 in adipose tissue were shown to be obese and insulin resistant. We recently observed that adipose tissue 11beta-HSD-1 mRNA expression is increased at the onset of high-fat diet-induced obesity and positively correlated with the degree of hyperglycemia. In human obesity, increased adipose tissue 11beta-HSD-1 expression and activity were also reported. Resistin is a new adipose tissue-secreted hormone shown to play a role in glucose homeostasis by increasing hepatic glucose production and inhibiting muscle and adipose tissue glucose utilization. We observed increased adipose tissue resistin expression in the early phase of high-fat diet-induced obesity as well as decreased resistin expression in response to leptin. A positive correlation between glycemia and adipose tissue resistin expression further suggested a role of this hormone in the development of insulin resistance. The melanocortin system is another important player in the regulation of energy balance. Peripheral administration of a melanocortin agonist decreased food intake and body weight and favored lipid oxidation, effects that were more marked in obese than in lean rats. It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11beta-HSD-1, thereby decreasing or enhancing glucose metabolism.
Assuntos
Tecido Adiposo/fisiopatologia , Glucocorticoides/fisiologia , Resistência à Insulina/fisiologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Sistema Nervoso Central/fisiopatologia , Dexametasona/metabolismo , Dexametasona/farmacologia , Glucocorticoides/metabolismo , Glucose/metabolismo , Homeostase/fisiologia , Hormônios Ectópicos/metabolismo , Humanos , Insulina/metabolismo , Camundongos , Neuropeptídeo Y/metabolismo , Ratos , Resistina , alfa-MSH/metabolismoAssuntos
Peso Corporal/fisiologia , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Sistemas Neurossecretores/fisiologia , Animais , Proteínas de Transporte/fisiologia , Homeostase , Humanos , Leptina/fisiologia , Glicoproteínas de Membrana/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Hormônios Tireóideos/fisiologiaRESUMO
BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART) is expressed within hypothalamic nuclei implicated in the regulation of feeding behaviour. It is up-regulated by leptin, and CART-derived peptides acutely inhibit food intake. OBJECTIVE: The present study was designed to assess the long-term effects of central CART administration on food intake, body weight, plasma levels of glucose, insulin, leptin, free fatty acids and triglycerides, and on fuel utilisation in normal and high-fat-fed obese rats. DESIGN: Normal and high-fat-fed obese rats were cannulated intracerebroventricularly (i.c.v.) and infused for 6 days with CART (55-102) or its vehicle. At day 4, animals were placed in an indirect calorimeter for a 24 h period during which the respiratory quotient and the energy expenditure were determined hourly. RESULTS: In both normal and obese animals, the chronic i.c.v. infusion of CART (55-102) had marked, sustained inhibitory effects on food intake and body weight gain that were accompanied by decreases in plasma insulin and leptin levels. Using indirect calorimetry, it was observed that CART infusion promoted an increase in lipid oxidation in normal and in obese animals, although this increase reached statistical significance only in the obese group. The hypothalamic CART mRNA expression was found to be higher in obese rats (displaying hyperleptinaemia) than in normal animals. CONCLUSION: The data together show that chronic i.c.v. CART infusion is effective in inhibiting food intake, favouring lipid oxidation and limiting fat storage, both in normal and high-fat-diet-induced obese rats. The CART pathway thus seems to be an important determinant of body weight homeostasis in normal animals as well as in a model of nutritionally induced obesity.
Assuntos
Ingestão de Energia/efeitos dos fármacos , Obesidade/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Glicemia/metabolismo , Northern Blotting , Peso Corporal/efeitos dos fármacos , Calorimetria Indireta , Ritmo Circadiano , Primers do DNA , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Regulação da Expressão Gênica , Bombas de Infusão Implantáveis , Insulina/sangue , Leptina/sangue , Masculino , Proteínas do Tecido Nervoso , Obesidade/genética , Fragmentos de Peptídeos/administração & dosagem , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Respiração , Triglicerídeos/sangueRESUMO
OBJECTIVE: The aims of the present study were to determine whether increased body weight resulting from intracerebroventricular (ICV) glucocorticoid (dexamethasone) infusion in normal rats is associated, as in obesity, with changes in glucose metabolism and to investigate whether the parasympathetic nervous system is involved in the glucocorticoid-induced effects. RESEARCH METHODS AND PROCEDURES: Male Sprague-Dawley rats were infused with ICV dexamethasone (2.5 microg/d) or its vehicle for 2 days during which food intake, body weight, and basal insulinemia were measured. Euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxyglucose technique were then performed to determine the total rate of glucose disappearance and the tissue glucose use indices. Similar experiments were carried out in vagotomized rats. RESULTS: Two days of ICV glucocorticoid infusion in normal rats resulted in increases in food intake, body weight, basal insulinemia, and produced decreases in the insulin-stimulated total rate of glucose disappearance, as well as in glucose use indices of all muscle types studied. None of these alterations was observed when glucocorticoid infusion was carried out in vagotomized rats. DISCUSSION: These data show that central glucocorticoid infusion favors anabolic processes, such as feeding behavior, body weight gain, and insulin output, while promoting muscle insulin resistance. These effects seem to be mediated by an activation of the parasympathetic nervous system, because they all disappear when tested in vagotomized rats.
Assuntos
Glicemia/metabolismo , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Resistência à Insulina/fisiologia , Obesidade/etiologia , Sistema Nervoso Parassimpático/fisiologia , Animais , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Técnica Clamp de Glucose , Bombas de Infusão , Masculino , Obesidade/fisiopatologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , VagotomiaRESUMO
The preferential channeling of different fuels to fat and changes in the transcription profile of adipose tissue and skeletal muscle are poorly understood processes involved in the pathogenesis of obesity and insulin resistance. Carbohydrate and lipid metabolism may play relevant roles in this context. Freely moving lean Zucker rats received 3- and 24-h infusions of Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, or saline plus heparin, to evaluate how an increase in free fatty acids (nonesterified fatty acid [NEFA]) modulates fat tissue and skeletal muscle gene expression and thus influences fuel partitioning. Glucose uptake was determined in various tissues at the end of the infusion period by means of the 2-deoxy-[1-3H]-D-glucose technique after a euglycemic-hyperinsulinemic clamp: high NEFA levels markedly decreased insulin-mediated glucose uptake in red fiber-type muscles but enhanced glucose utilization in visceral fat. Using reverse transcriptase-polymerase chain reaction and Northern blotting analyses, the mRNA expression of fatty acid translocase (FAT)/CD36, GLUT4, tumor necrosis factor (TNF)-alpha, peroxisome proliferator-activated receptor (PPAR)-gamma, leptin, uncoupling protein (UCP)-2, and UCP-3 was investigated in different fat depots and skeletal muscles before and after the study infusions. GLUT4 mRNA levels significantly decreased (by approximately 25%) in red fiber-type muscle (soleus) and increased (by approximately 45%) in visceral adipose tissue. Furthermore, there were marked increases in FAT/CD36, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 mRNA levels in the visceral fat and muscle of the treated animals in comparison with those measured in the saline-treated animals. These data suggest that the in vivo gene expression of FAT/CD36, GLUT4, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 in visceral fat and red fiber-type muscle are differently regulated by circulating lipids and that selective insulin resistance seems to favor, at least in part, a prevention of fat accumulation in tissues not primarily destined for fat storage, thus contributing to increased adiposity and the development of a prediabetic syndrome.
Assuntos
Tecido Adiposo/metabolismo , Metabolismo Energético , Ácidos Graxos não Esterificados/farmacocinética , Músculo Esquelético/metabolismo , Tecido Adiposo/fisiologia , Animais , Emulsões Gordurosas Intravenosas/farmacocinética , Emulsões Gordurosas Intravenosas/farmacologia , Expressão Gênica/efeitos dos fármacos , Técnica Clamp de Glucose , Heparina/farmacologia , Masculino , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiologia , Ratos , Ratos Zucker , VíscerasRESUMO
Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity.
Assuntos
Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Leptina/fisiologia , Neuropeptídeos/fisiologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Hormônios Hipotalâmicos/fisiologia , Leptina/uso terapêutico , Melaninas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neuropeptídeo Y/fisiologia , Peptídeos Opioides/fisiologia , Hormônios Hipofisários/fisiologia , alfa-MSH/fisiologiaRESUMO
Leptin acts as a satiety factor within the central nervous system by binding to its receptor located in the hypothalamus. A missense mutation of the leptin receptor induces hyperphagia and obesity in the obese Zucker fa/fa rat. Since the CNS is an important target of leptin action, we hypothesized that leptin gene transfer into the lateral cerebral ventricle could efficiently lead to inhibition of food intake and reduction of body weight in obese fa/fa rats as well as in lean animals. A single intracerebroventricular injection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the first week after injection, when high concentrations of leptin were produced in the CSF, the reducing effects of leptin on food intake and body weight were comparable in lean and in obese fa/fa rats. The subsequent decline in CSF leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese group. The results of this study show that leptin gene delivery into the cerebral ventricles allows for the production of elevated leptin concentrations in CSF, and they support the hypothesis that the impaired sensitivity to leptin may be overcome in obese fa/fa rats.
Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Leptina/metabolismo , Obesidade/metabolismo , Adenoviridae , Animais , Ventrículos Cerebrais/metabolismo , Feminino , Expressão Gênica , Vetores Genéticos , Injeções Intraventriculares , Leptina/genética , Camundongos , Ratos , Ratos Zucker , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
A loop system exists between hypothalamic neuropeptide Y (NPY) and peripheral adipose tissue leptin to maintain normal body homeostasis. When hypothalamic NPY levels are increased by fasting or by intracerebroventricular (i.c.v.) infusion, food intake and body weight increase. NPY has genuine hormono-metabolic effects. It increases insulin and corticosterone secretion relative to controls. These hormonal changes, acting singly or combined, favor adipose tissue lipogenic activity, while producing muscle insulin resistance. They also promote leptin release from adipose tissue. When infused i.c.v. to normal rats to mimic its central effects, leptin decreases NPY levels, thus food intake and body weight. Leptin i.c.v. has also genuine hormono-metabolic effects. It decreases insulinemia and adipose tissue storage ability, enhancing glucose disposal. Leptin increases the expression of uncoupling proteins (UCP-1, -2, -3) and thus energy dissipation. Leptin-induced changes favor oxidation at the expense of storage. Circadian fluctuations of NPY and leptin levels maintain normal body homeostasis. In animal obesity, defective hypothalamic leptin receptor activation prevent leptin from acting, with resulting obesity, insulin and leptin resistance.
Assuntos
Metabolismo Energético , Leptina/fisiologia , Neuropeptídeo Y/fisiologia , Tecido Adiposo/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Jejum , Leptina/administração & dosagem , Neuropeptídeo Y/administração & dosagem , Desacopladores/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
The obesity-like effects produced by the chronic intracerebroventricular (i.c.v.) neuropeptide Y (NPY) infusion in normal rats require the presence of glucocorticoids, as none of them occurs when NPY is similarly infused in adrenalectomized rats. NPY effects are present again when i.c.v. NPY is infused together with i.c.v. dexamethasone in adrenalectomized animals. The inhibitory effect of leptin on food intake and body weight observed when the hormone is i.c.v. administered to normal rats is markedly enhanced and longer lasting when the same dose of leptin is i.c.v. administered to adrenalectomized rats. Glucocorticoid administration to adrenalectomized rats dose-dependently reduces, then abolishes, this potent effect of leptin. Thus, glucocorticoids limit leptin-induced effects. The chronic i.c.v. infusion of glucocorticoids (dexamethasone) to normal rats produces an obesity syndrome with its several abnormalities. This appears to be due to glucocorticoid-elicited increases in hypothalamic NPY levels together with decreases in those of CRH. Thus, the status of the hypothalamo-pituitary-adrenal axis and related glucocorticoid output is a relevant facet of body weight homeostasis. It may be a deleterious environmental factor responsible for the development of obesity, insulin as well as leptin resistance, and type 2 diabetes.
Assuntos
Peso Corporal , Sistema Nervoso Central/fisiologia , Glucocorticoides/fisiologia , Homeostase , Sistema Nervoso Periférico/fisiologia , Animais , Glucocorticoides/administração & dosagem , Resistência à Insulina , Leptina/farmacologia , Neuropeptídeo Y/farmacologia , Obesidade/induzido quimicamente , RatosRESUMO
We have shown previously that continuous (6 days) intracerebroventricular (ICV) leptin infusion in normal rats resulted in decreases in food intake and body weight. A reduction of food intake imposed on control rats (pair-feeding), aimed at mimicking leptin-induced hyperphagia, produced a marked decrease in the expression of muscle uncoupling protein-3 (UCP-3), whereas ICV infusion of leptin prevented such a decrease in UCP-3. To investigate an involvement of thyroid hormones in this effect of leptin, plasma levels of these hormones were determined in ICV leptin-infused, ICV vehicle-infused ad libitum fed or pair-fed controls. ICV leptin infusion and pair-feeding resulted in decreased plasma thyroid-stimulating hormone (TSH) and T4 levels relative to ad libitum fed controls. ICV leptin infusion maintained plasma levels of T3, but the levels were decreased by pair-feeding. The activity of the enzyme (hepatic 5'-monodeiodinase) responsible for T4/T3 conversion was measured. In the leptin-infused group, the activity of 5'-monodeiodinase was maintained at the values measured in ad libitum fed rats; in pair-fed rats, activity was reduced. Thus, conversion of T4 to T3 is decreased by pair-feeding, whereas such is not the case during leptin infusion. To further substantiate an involvement of thyroid hormones in the effect of leptin on muscle UCP-3 expression, hypothyroid rats were ICV infused with leptin or vehicle. It was observed that in hypothyroid rats, ICV leptin was unable to maintain muscle UCP-3 expression at values measured in ad libitum fed controls. These results suggest that central leptin stimulates T3 production via an activation of T4 to T3 conversion, and that this stimulation could be responsible for the effect of leptin on muscle UCP-3 expression. Thyroid hormones could thus be important mediators of the effect of leptin on energy expenditure.