RESUMO
CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22-Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹8F-FDG-PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2.
Assuntos
Tecido Adiposo Marrom/metabolismo , Quimiocina CCL22/genética , Febre/fisiopatologia , Hipotálamo Anterior/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Temperatura Corporal/efeitos dos fármacos , Quimiocina CCL22/metabolismo , Quimiocina CCL22/farmacologia , Dinoprostona/metabolismo , Feminino , Febre/induzido quimicamente , Febre/prevenção & controle , Expressão Gênica , Hipotálamo Anterior/efeitos dos fármacos , Indometacina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Pirogênios/metabolismo , Pirogênios/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores CCR4/genética , Receptores CCR4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telemetria , Tomografia Computadorizada por Raios XRESUMO
We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Receptores da Colecistocinina/agonistas , Animais , Fármacos Antiobesidade/farmacocinética , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916±952 pg/mL vs. 23474±1507 pg/mL, P<.01) while no change was observed for insulin, IGF-1 or leptin. GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of its down-regulation.
Assuntos
Adiponectina/sangue , Regulação da Temperatura Corporal , Área Pré-Óptica/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Regulação para Baixo , Fator de Crescimento Insulin-Like I/análise , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Aumento de PesoRESUMO
Adiponectin can act in the brain to increase energy expenditure and reduce body weight by mechanisms not entirely understood. We found that adiponectin type 1 and type 2 receptors (AdipoR1 and AdipoR2) are expressed in warm sensitive neurons of the hypothalamic preoptic area (POA) which play a critical role in the regulation of core body temperature (CBT) and energy balance. Thus, we tested the ability of adiponectin to influence CBT in wild-type mice and in mice deficient for AdipoR1 or AdipoR2. Local injection of adiponectin into the POA induced prolonged elevation of core body temperature and decreased respiratory exchange ratio (RER) indicating that increased energy expenditure is associated with increased oxidation of fat over carbohydrates. In AdipoR1 deficient mice, the ability of adiponectin to raise CBT was significantly blunted and its ability to decrease RER was completely lost. In AdipoR2 deficient mice, adiponectin had only diminished hyperthermic effects but reduced RER similarly to wild type mice. These results indicate that adiponectin can contribute to energy homeostasis by regulating CBT by direct actions on AdipoR1 and R2 in the POA.