Garcia-Souza Erica Patrícia, da Silva Simone Vargas, Félix Gisele Barreto, Rodrigues Ananda Lages, de Freitas Marta Sampaio, Moura Aníbal Sanchez, Barja-Fidalgo Christina
Departament of Pharmacology, Institute of Biology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, 20551-030, Brasil.
Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E626-36. doi: 10.1152/ajpendo.00439.2007. Epub 2008 Jun 17.
Epidemiological and experimental studies have demonstrated that early postnatal nutrition has been associated with long-term effects on glucose homeostasis in adulthood. Recently, our group demonstrated that undernutrition during early lactation affects the expression and activation of key proteins of the insulin signaling cascade in rat skeletal muscle during postnatal development. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity in peripheral tissues, we investigated the insulin signaling in adipose tissue. Adipocytes were isolated from epididymal fat pads of adult male rats that were the offspring of dams fed either a normal or a protein-free diet during the first 10 days of lactation. The cells were incubated with 100 nM insulin before the assays for immunoblotting analysis, 2-deoxyglucose uptake, immunocytochemistry for GLUT4, and/or actin filaments. Following insulin stimulation, adipocytes isolated from undernourished rats presented reduced tyrosine phosphorylation of IR and IRS-1 and increased basal phosphorylation of IRS-2, Akt, and mTOR compared with controls. Basal glucose uptake was increased in adipocytes from the undernourished group, and the treatment with LY294002 induced only a partial inhibition both in basal and in insulin-stimulated glucose uptake, suggesting an involvement of phosphoinositide 3-kinase activity. These alterations were accompanied by higher GLUT4 content in the plasma membrane and alterations in the actin cytoskeleton dynamics. These data suggest that early postnatal undernutrition impairs insulin sensitivity in adulthood by promoting changes in critical steps of insulin signaling in adipose tissue, which may contribute to permanent changes in glucose homeostasis.
流行病学和实验研究表明，出生后早期营养与成年期葡萄糖稳态的长期影响有关。最近，我们的研究小组表明，早期哺乳期营养不良会影响出生后发育期间大鼠骨骼肌中胰岛素信号级联关键蛋白的表达和激活。为了阐明生命早期营养不良导致外周组织胰岛素敏感性变化的分子机制，我们研究了脂肪组织中的胰岛素信号。从成年雄性大鼠的附睾脂肪垫中分离脂肪细胞，这些大鼠是在哺乳期前10天喂食正常饮食或无蛋白饮食的母鼠的后代。在进行免疫印迹分析、2-脱氧葡萄糖摄取、GLUT4免疫细胞化学和/或肌动蛋白丝检测之前，将细胞与100 nM胰岛素一起孵育。胰岛素刺激后，与对照组相比，从营养不良大鼠分离的脂肪细胞显示IR和IRS-1的酪氨酸磷酸化降低，IRS-2、Akt和mTOR的基础磷酸化增加。营养不良组脂肪细胞的基础葡萄糖摄取增加，LY294002处理仅对基础和胰岛素刺激的葡萄糖摄取诱导部分抑制，提示磷酸肌醇3激酶活性参与其中。这些改变伴随着质膜中GLUT4含量的增加和肌动蛋白细胞骨架动力学的改变。这些数据表明，出生后早期营养不良通过促进脂肪组织中胰岛素信号关键步骤的变化，损害成年期胰岛素敏感性，这可能导致葡萄糖稳态的永久性变化。
