RESUMO
Glucose is a major energy source for growth. At birth, neonates must change their energy source from maternal supply to its own glucose production. The mechanism of this transition has not been clearly elucidated. To evaluate the possible roles of steroids in this transition, here we examine the defects associated with energy production of a mouse line that cannot synthesize steroids de novo due to the disruption of its Cyp11a1 (cytochrome P450 family 11 subfamily A member 1) gene. The Cyp11a1 null embryos had insufficient blood insulin and failed to store glycogen in the liver since embryonic day 16.5. Their blood glucose dropped soon after maternal deprivation, and the expression of hepatic gluconeogenic and glycogenic genes were reduced. Insulin was synthesized in the mutant fetal pancreas but failed to be secreted. Maternal glucocorticoid supply rescued the amounts of blood glucose, insulin, and liver glycogen in the fetus but did not restore expression of genes for glycogen synthesis, indicating the requirement of de novo glucocorticoid synthesis for glycogen storage. Thus, our investigation of Cyp11a1 null embryos reveals that the energy homeostasis is established before birth, and fetal steroids are required for the regulation of glycogen synthesis, hepatic gluconeogenesis, and insulin secretion at the fetal stage.
Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Esteroides/biossíntese , Esteroides/farmacologia , Animais , Animais Recém-Nascidos , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Dexametasona/farmacologia , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Metabolismo Energético/genética , Feminino , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Glicogênio/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Central memory T lymphocytes were reported to develop after acute but not chronic infection, which prompted this feasibility study on generating long-term CD8 T cells ex vivo, by applying a culture condition that simulates an acute infection. During 35 d of culture, naive T cells (CD45RA(+), CD127(+), CCR7(+), CD62L(+), CXCR3(+)) first developed into effector T cells (CD45RA(+/-), CD127(+/-), CCR7(+/-), CD62L(+), CXCR3(+)), followed by three intermediate stages: intermediate T cells 1 (CD45RO(+), CD127(+/-), CCR7(+), CD62L(+), CXCR3(+)), intermediate T cells 2 (CD45RO(+), CD127(-), CCR7(-), CD62L(+), CXCR3(+)), and intermediate T cells 3 (CD45RO(+/-), CD127(+), CCR7(+), CD62L(-), CXCR3(+)) before reverting to stable CD45RA(+) central memory T cells (CD45RA(+), CD127(+), CCR7(+), CD62L(+), CXCR3(+)). If both anti-CD3 and the inflammatory milieu persisted beyond day 10, intermediate T cells 2 gradually developed into effector memory T cells (CD45RO(+), CD127(-), CCR7(-), CD62L(-), CXCR3(+)). Furthermore, intermediate T cells 2 or effector memory T cells, when cultured in persistent inflammatory cytokines devoid of anti-CD3, were converted to central memory T cells (CD45RO(+), CCR7(+), CD62L(+)). Overall, these results support ex vivo memory-like T lymphocyte production and favor a developmental pathway including both divergent and linear relationships.
