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1.
J Clin Invest ; 124(10): 4473-88, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25202980

RESUMO

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptores de Glucagon/metabolismo , Redução de Peso/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Eletrofisiologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipotálamo/metabolismo , Liraglutida , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Vago/metabolismo
2.
Endocrinology ; 151(4): 1473-86, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20203154

RESUMO

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.


Assuntos
Calcitonina/metabolismo , Proliferação de Células/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptores de Glucagon/metabolismo , Glândula Tireoide/efeitos dos fármacos , Animais , Western Blotting , Calcitonina/genética , Linhagem Celular , Células Cultivadas , AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Liraglutida , Macaca fascicularis , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Receptores de Glucagon/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Glândula Tireoide/citologia , Glândula Tireoide/metabolismo
3.
Eur J Pharmacol ; 440(2-3): 159-72, 2002 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-12007533

RESUMO

Although most humans experience an underlying upwards drift of the body-weight set-point, body weight appears tightly regulated throughout life. The present review describes the structural basis of the adipostat and hypothesise, which components may constitute available targets for pharmacotherapy of excess body weight. Hypothalamic neurones constitute the major components of the body weight homeostasis maintaining device. Together with neurones of the nucleus of the solitary tract, neurones of the hypothalamic arcuate nucleus constitute the sensory components of the adipostat. The arcuate nucleus neurones respond to circulating levels of leptin and insulin, both of which reflect the levels of energy stored as triacylglycerol in adipocytes. The arcuate nucleus projects heavily to the hypothalamic paraventricular nucleus. Neurones of the hypothalamic paraventricular nucleus are hypothesised to constitute, at least partly, the adipostat motor pattern generator, which upon stimulation activates either net anabolic or catabolic physiological responses. The overall sensitivity of the adipostat is influenced by gain setting neurones hypothesised to be located in the dorsomedial hypothalamic nucleus and lateral hypothalamic area. Cocaine amphetamine regulated transcript (CART) peptides and pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are catabolic neurotransmitters synthesised in neurones of the arcuate nucleus and the nucleus of the solitary tract, respectively. The present review summarises the available evidence that both families of peptides constitute endogenous transmitters mediating satiety and touch upon potential pharmacological exploitation of this knowledge.


Assuntos
Peso Corporal/fisiologia , Neuropeptídeos/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon , Peptídeo 2 Semelhante ao Glucagon , Homeostase/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Precursores de Proteínas/farmacologia
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