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1.
Neuroscience ; 247: 43-54, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23701881

RESUMO

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity.


Assuntos
Tronco Encefálico/metabolismo , Diabetes Mellitus Tipo 2/sangue , Ingestão de Alimentos/fisiologia , Hormônio Liberador de Tireotropina/fisiologia , Nervo Vago/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum/sangue , Masculino , Ratos , Ratos Wistar
2.
Neuroscience ; 169(2): 706-19, 2010 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-20457219

RESUMO

We identified ventrolateral medullary nuclei in which thyrotropin-releasing hormone (TRH) regulates glucose metabolism by modulating autonomic activity. Immunolabeling revealed dense prepro-TRH-containing fibers innervating the rostroventrolateral medulla (RVLM) and nucleus ambiguus (Amb), which contain, respectively, pre-sympathetic motor neurons and vagal motor neurons. In anesthetized Wistar rats, microinjection of the stable TRH analog RX77368 (38-150 pmol) into the RVLM dose-dependently and site-specifically induced hyperglycemia and hyperinsulinemia. At 150 pmol, blood glucose reached a peak of 180+/-18 mg% and insulin increased 4-fold. The strongest hyperglycemic effect was induced when RX77368 was microinjected into C1 area containing adrenalin cells. Spinal cord transection at cervical-7 abolished the hyperglycemia induced by RVLM RX77368, but not the hyperinsulinemic effect. Bilateral vagotomy prevented the rise in insulin, resulting in a prolonged hyperglycemic response. The hyperglycemic and hyperinsulinemic effects of the TRH analog in the RVLM was peptide specific, since angiotensin II or a substance P analog at the same dose had weak or no effects. Microinjection of RX77368 into the Amb stimulated insulin secretion without influencing glucose levels. In conscious type 2 diabetic Goto-Kakizaki (GK) rats, intracisternal injection of RX77368 induced a remarkably amplified hyperglycemic effect with suppressed insulin response compared to Wistar rats. RX77368 microinjected into the RVLM of anesthetized GK rats induced a significantly potentiated hyperglycemic response and an impaired insulin response, compared to Wistar rats. These results indicate that the RVLM is a site at which TRH induces sympathetically-mediated hyperglycemia and vagally-mediated hyperinsulinemia, whereas the Amb is mainly a vagal activating site for TRH. Hyperinsulinemia induced by TRH in the RVLM is not secondary to the hyperglycemic response. The potentiated hyperglycemic and suppressed hyperinsulinemic responses in diabetic GK rats indicate that an unbalanced "sympathetic-over-vagal" activation by TRH in brainstem RVLM contributes to the pathophysiology of impaired glucose homeostasis in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Bulbo/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Hormônio Liberador de Tireotropina/análogos & derivados , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/fisiopatologia , Hiperinsulinismo/fisiopatologia , Insulina/sangue , Masculino , Bulbo/efeitos dos fármacos , Microinjeções , Fibras Nervosas/metabolismo , Vias Neurais/fisiopatologia , Precursores de Proteínas/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Ácido Pirrolidonocarboxílico/farmacologia , Ratos , Ratos Wistar , Medula Espinal/fisiopatologia , Hormônio Liberador de Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/farmacologia , Nervo Vago/fisiopatologia
3.
Exp Biol Med (Maywood) ; 230(8): 558-68, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16118406

RESUMO

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.


Assuntos
Neoplasias da Mama/fisiopatologia , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Fitoestrógenos/farmacologia , Adenocarcinoma , Linhagem Celular Tumoral , Estradiol/farmacologia , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/genética , Feminino , Humanos , Mutagênese Sítio-Dirigida , Plasmídeos , Mutação Puntual , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Ativação Transcricional , Transfecção
4.
Br J Cancer ; 91(12): 2094-100, 2004 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-15599384

RESUMO

Inhibitors of glycogen breakdown regulate glucose homeostasis by limiting glucose production in diabetes. Here we demonstrate that restrained glycogen breakdown also inhibits cancer cell proliferation and induces apoptosis through limiting glucose oxidation, as well as nucleic acid and de novo fatty acid synthesis. Increasing doses (50-100 microM) of the glycogen phosphorylase inhibitor CP-320626 inhibited [1,2-(13)C(2)]glucose stable isotope substrate re-distribution among glycolysis, pentose and de novo fatty acid synthesis in MIA pancreatic adenocarcinoma cells. Limited oxidative pentose-phosphate synthesis, glucose contribution to acetyl CoA and de novo fatty acid synthesis closely correlated with decreased cell proliferation. The stable isotope-based dynamic metabolic profile of MIA cells indicated a significant dose-dependent decrease in macromolecule synthesis, which was detected at lower drug doses and before the appearance of apoptosis markers. Normal fibroblasts (CRL-1501) did not show morphological or metabolic signs of apoptosis likely due to their slow rate of growth and metabolic activity. This indicates that limiting carbon re-cycling and rapid substrate mobilisation from glycogen may be an effective and selective target site for new drug development in rapidly dividing cancer cells. In conclusion, pancreatic cancer cell growth arrest and death are closely associated with a characteristic decrease in glycogen breakdown and glucose carbon re-distribution towards RNA/DNA and fatty acids during CP-320626 treatment.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Amidas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicogênio Fosforilase/antagonistas & inibidores , Glicólise/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Indóis
5.
Diabetes Obes Metab ; 5(5): 317-24, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12940869

RESUMO

AIMS: The specific objective of this study was to determine acute and long-term effects of cyclo (his-pro) (CHP) plus zinc and l-histidine (CZH) treatment on glucose metabolism in genetically obese (ob/ob), type 2 diabetic mice. METHODS: Acute effects of 0.3 mg of CHP plus 10 mg of zinc and 0.5 mg of l-histidine/kg body weight (BW) on fed blood glucose concentrations and 3-h average of above fasting blood glucose concentrations (TAFGCs), an index of oral glucose tolerance test, in lean and ob/ob mice were determined. To evaluate long-term effects of CZH on TAFGCs, lean and ob/ob mice were treated with drinking water containing increasing doses of CHP (0, 0.5, 1.0 or 1.5 mg/l) plus 10 mg zinc and 0.5 mg of l-histidine/l for 3 weeks. During the treatment period, fed blood glucose concentrations, BW and food and water intake were determined. At the end of the treatment, fasting blood glucose concentrations, TAFGC and fed plasma insulin concentrations were determined. RESULTS: Blood glucose concentrations significantly decreased when CZH was administered acutely via gastric gavage in food-deprived ob/ob mice. Similarly, 1.0 mg/l CHP treatment of mice with fixed amounts of 10 mg zinc and 0.5 mg l-histidine/l was optimal to decrease fed blood glucose and plasma insulin concentrations during a 3-week treatment period in ob/ob mice. TAFGC values in these mice also improved most significantly with the same combination of CHP, zinc and l-histidine used to test for fed blood glucose and plasma insulin levels. Fasting blood glucose concentrations and BW gains also decreased in ob/ob mice treated with 1.0 mg of CHP/l plus the same amount of zinc and l-histidine used in the above experiments. No effects of CZH treatment in lean mice were observed. CONCLUSIONS: CZH is effective in decreasing blood glucose concentrations in genetically obese (ob/ob), type 2 diabetic mice. These data support our working hypothesis that CZH may be an important anti-hyperglycaemic agent.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade , Peptídeos Cíclicos/uso terapêutico , Piperazinas/uso terapêutico , Zinco/uso terapêutico , Animais , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Aumento de Peso/efeitos dos fármacos
6.
Pancreas ; 25(4): 405-10, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12409837

RESUMO

INTRODUCTION AND AIMS: Orexins have been demonstrated to have mainly central physiological functions, including regulation of food and water intake, sleep, and arousal. However, little is known about their direct peripheral effects, if any. As a first step toward understanding the role of Orexin in non-neuronal tissues or cells, we initiated studies to examine expression of Orexin receptors (OXR) in an established pancreatic tumor cell line AR42J. Secondly, we wanted to determine whether Orexins, in various molecular forms, are active to stimulate any known pancreatic cell functions in AR42J cells. METHODOLOGY: Reverse transcription-PCR analysis was performed to identify the presence of specific Orexin receptor subtypes. Intracellular calcium mobilization and cAMP levels were measured following stimulation by Orexin A and B peptides, their respective C-terminal decapeptide fragments, and hypocretin-2-gly (glycine-extended Orexin B). Release of alpha-amylase was measured in conditioned media after acute stimulation with the set of Orexin peptides for 30 minutes. Cell proliferation was determined by H-thymidine incorporation after 24 hours following treatment with Orexins under serum-free condition. RESULTS: RT-PCR and sequencing results showed that Orexin receptor subtype 2 (OX2R) was the main form expressed in AR42J cells. Orexins stimulated dose-dependent increases in intracellular calcium mobilization with EC50 0.05 nM for Orexin A and 0.1 nM for Orexin B but were unable to stimulate any significant cAMP accumulation or DNA synthesis even at micromolar concentrations. Both Orexin-A and -B, but not hypocretin-2-gly, also stimulated dose-dependent increases in amylase release in the AR42J cells. Orexin-A and -B carboxyl-terminal decapeptides elicited significant but much lower calcium and amylase responses. CONCLUSION: Our data demonstrate that OX2R mediates Ca -dependent amylase release in AR42J cells, suggesting that Orexins may have secretory functions in pancreatic tumor cells.


Assuntos
Amilases/metabolismo , Proteínas de Transporte/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Neuropeptídeos/farmacologia , Pâncreas/enzimologia , Receptores de Neuropeptídeos/fisiologia , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Proteínas de Transporte/genética , AMP Cíclico/análise , Relação Dose-Resposta a Droga , Dados de Sequência Molecular , Neuropeptídeos/genética , Receptores de Orexina , Orexinas , Pâncreas/química , Pâncreas/efeitos dos fármacos , RNA Mensageiro/biossíntese , Ratos , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/genética , Alinhamento de Sequência , Células Tumorais Cultivadas
7.
Diabetes Obes Metab ; 4(2): 124-31, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11940110

RESUMO

AIM: The present study is designed to determine whether arachidonic acid (AA) plus zinc improves clinical signs of diabetes in genetically diabetic ob/ob mice. METHODS: In the first study, effects of acute administration of AA plus zinc on glucose disposal were determined in ob/ob and lean mice (n = 6 each). In the second study, ob/ob and lean mice were treated with increasing doses of AA plus zinc for 2 weeks (n = 5 each). Postprandial and fasting blood glucose concentrations, three-hour-area-average above fasting glucose concentration (TAFGC), water and food intake, body weight and plasma insulin concentrations were measured. RESULTS: Acute administration of AA plus zinc significantly increased glucose disposal in ob/ob mice. In the second study, postprandial and fasting blood glucose concentrations, TAFGC, and water and food intake in ob/ob mice treated with AA plus zinc for 2 weeks were significantly decreased compared with those in mice given no AA. Plasma insulin concentrations in both lean and ob/ob mice were not changed by AA treatment in drinking water. CONCLUSIONS: AA plus zinc in drinking water is effective in decreasing blood glucose levels in obese mice. These results indicate that use of these compounds should be considered as a dietary supplement to control hyperglycaemia in patients with type II diabetes.


Assuntos
Ácido Araquidônico/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus/genética , Obesidade , Zinco/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus/sangue , Jejum , Teste de Tolerância a Glucose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Período Pós-Prandial
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