RESUMO
Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.
Assuntos
Proteínas de Transporte/fisiologia , Músculo Esquelético/fisiologia , Tecido Adiposo/metabolismo , Animais , Animais Geneticamente Modificados , Glicemia/metabolismo , Proteínas de Transporte/genética , Metabolismo Energético , Feminino , Humanos , Hiperfagia/genética , Canais Iônicos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais , Fenótipo , Magreza , Proteína Desacopladora 3Assuntos
Proteínas de Drosophila , Proteínas de Ligação ao GTP/fisiologia , Proteínas de Membrana/classificação , Receptores de Superfície Celular/fisiologia , Receptores dos Hormônios Gastrointestinais/classificação , Sequência de Aminoácidos , Animais , Receptores Frizzled , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/fisiologia , Dados de Sequência Molecular , Receptores Acoplados a Proteínas G , Receptores dos Hormônios Gastrointestinais/química , Rodopsina/classificação , Transdução de SinaisRESUMO
The role of beta3- and other putative atypical beta-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine beta3-adrenoceptor (beta3AR) agonists with varying intrinsic activities and selectivities for human cloned betaAR subtypes. The ability to demonstrate beta1/2AR antagonist-insensitive (beta3 or other atypical betaAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective beta3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited beta1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full beta3AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta1/2AR antagonism, despite it having very low efficacies at cloned beta1- and beta2ARs. A component of the response to another phenylethanolamine selective beta3AR agonist (SB-215691) was insensitive to beta1/2AR antagonism in some experiments. Because no [corrected] novel aryloxypropanolamine had a beta1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that beta3ARs mediate lipolysis in human white adipocytes, and suggest that putative 'beta4ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned betaARs which betaARs will mediate responses to agonists in tissues that have a high number of beta1- and beta2ARs or a low number of beta3ARs.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Função do Átrio Direito/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Etanolaminas/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propanolaminas/farmacologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/fisiologiaRESUMO
Extrapolating systematically from gene sequence to function is undoubtedly the major challenge facing industry and academia alike as we approach the end of the millennium. Many electronic and laboratory approaches are being developed to meet this challenge but the rate of evolution of these is not keeping pace with the speed of sequence generation.
Assuntos
Biologia Computacional/tendências , Bases de Dados como Assunto , Genética/tendências , Genoma , Animais , Genes/fisiologia , Humanos , PesquisaRESUMO
The chiral synthesis of the potent and selective alpha-2A antagonist, BRL 48962, is described. Evaluation of BRL 48962 at cloned human alpha-adrenoceptors indicates that this antagonist has a selectivity in the order of 30-fold for the alpha-2A subtype.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tecido Adiposo/metabolismo , Antagonistas Adrenérgicos alfa/química , Animais , Aorta/metabolismo , Plaquetas/metabolismo , Células CHO , Córtex Cerebral/metabolismo , Clonagem Molecular , Cricetinae , Humanos , Imidazóis/química , Técnicas In Vitro , Indóis/química , Isoindóis , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Coelhos , Ratos , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , EstereoisomerismoRESUMO
The biological activities of GA40, GA43, GA46, GA47, GA51 and GA4 20,4-lactone were tested over a wide range of concentrations in six plant bioassays. GA4 20,4-lactone showed the highest activity. Of the two 2α-hydroxylated compounds GA47 showed moderately high activity, and GA40 was slightly active. The 2ß-hydroxylated compunds GA43, GA46 and GA51 were virtually inactive.
