Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto-Kakizaki rats.
Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto-Kakizaki rats.
复制标题
VMH中脑衍生的神经营养因子是治疗2型糖尿病goto-kakizaki大鼠的内脏肥胖和高稀释血症的因果因素和治疗工具。
DOI：
10.3389/fnsyn.2013.00007
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发表时间：
2013
影响因子：
3.7
通讯作者：
Yada T
中科院分区：
文献类型：
--
作者：
Maekawa F;Fujiwara K;Toriya M;Maejima Y;Nishio T;Toyoda Y;Nohara K;Yashiro T;Yada T
我们先前报道了2型糖尿病Goto-Kakizaki（GK）大鼠在年轻成年期（6-12周龄）表现出内脏脂肪量增加和高瘦素血症，这主要是由于下丘脑弓状核神经肽Y（NPY）过度表达引起的摄食过多。后来，我们发现，GK大鼠继续表现出肠系膜脂肪堆积和高瘦素血症，至少直到26周龄，而暴食症和神经肽Y过度表达停止在15周龄。因此，我们推测，长期的脂肪积累和高瘦素血症是由于不明的脑功能障碍，而不是NPY过表达。在26周龄GK大鼠中，下丘脑腹内侧（VMH）葡萄糖转运蛋白-2（GLUT 2）mRNA的表达明显减少，与此同时，VMH中脑源性神经营养因子（BDNF）mRNA水平和BDNF表达细胞数量显著减少。在体内和体外，药物抑制葡萄糖利用减少VMH中BDNF mRNA的表达。结果提示，糖利用障碍可引起脑源性神经营养因子的减少。在另一方面，脑室内注射BDNF 6天改善高瘦素血症在一个持久的方式与喂养抑制同时在GK大鼠。限制喂养配对BDNF治疗的大鼠血浆瘦素水平只短暂降低。BDNF治疗也减少了GK大鼠肠系膜脂肪量。这些结果揭示了一种新的作用模式，BDNF长期持久地抵消内脏肥胖和高瘦素血症，除了和独立于其促肥胖作用。这些结果表明，内脏脂肪堆积和高瘦素血症至少部分是由于减少BDNF的VMH主要是由受损的葡萄糖利用GK大鼠。补充BDNF可有效治疗2型糖尿病内脏肥胖、高瘦素血症和瘦素抵抗。
We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK rats continued to exhibit mesenteric fat accumulation and hyperleptinemia at least until 26 weeks of age, while hyperphagia and NPY overexpression ceased at 15 weeks of age. Therefore, we hypothesized that the long-lasting fat accumulation and hyperleptinemia are due to unidentified brain dysfunction other than NPY overexpression. In GK rats aged 26 weeks, glucose transporter-2 (GLUT2) mRNA expression in ventromedial hypothalamus (VMH) was markedly reduced in parallel with significant decreases in brain-derived neurotrophic factor (BDNF) mRNA level and BDNF-expressing cell numbers in the VMH. Pharmacologic inhibition of glucose utilization reduced BDNF mRNA expression in VMH in vivo and in vitro. The results suggested that impaired glucose utilization caused the reduction of BDNF. On the other hand, intracerebroventricular injection of BDNF for 6 days ameliorated hyperleptinemia in a long-lasting manner concurrently with feeding suppression in GK rats. Restricted feeding paired to BDNF-treated rats reduced plasma leptin level only transiently. BDNF treatment also reduced mesenteric fat mass in GK rats. These results reveal a novel action mode of BDNF to long-lastingly counteract visceral adiposity and hyperleptinemia in addition to and independently of its anorexigenic action. These results suggest that visceral fat accumulation and hyperleptinemia are at least partly due to the reduction of BDNF in VMH primarily caused by impaired glucose utilization in GK rats. The BDNF supplementation could provide an effective treatment of visceral obesity, hyperleptinemia and leptin resistance in type 2 diabetes.