Leptin Action in the Ventromedial Hypothalamic Nucleus Is Sufficient, But Not Necessary, to Normalize Diabetic Hyperglycemia
Leptin Action in the Ventromedial Hypothalamic Nucleus Is Sufficient, But Not Necessary, to Normalize Diabetic Hyperglycemia
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DOI：
10.1210/en.2013-1328
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发表时间：
2013-09-01
期刊：
影响因子：
4.8
通讯作者：
Morton, Gregory J.
中科院分区：
文献类型：
--
作者：
Meek, Thomas H.;Matsen, Miles E.;Morton, Gregory J.
在1型糖尿病的啮齿动物模型中，瘦素在脑室给药使血糖正常化，而在外周给药时没有效果。下丘脑腹内侧核（VMN）是瘦素抗糖尿病作用的潜在靶点，因为该脑区的瘦素敏感神经元与葡萄糖稳态有关。为了验证这一假设，我们将瘦素直接注射到链脲佐菌素诱导的糖尿病大鼠的双侧VMN中。这种干预完全正常化高血糖症和肝葡萄糖产生率和血浆胰高血糖素水平的升高，但对骨骼肌或棕色脂肪组织中的组织葡萄糖摄取没有影响，如在基础钳夹期间使用示踪剂稀释技术所测量的。为了确定是否VMN瘦素信号是必需的瘦素介导的糖尿病高血糖症的正常化，我们研究了小鼠中的瘦素受体基因被删除VMN类固醇生成因子1神经元使用cre-loxP技术。我们的研究结果表明，这些神经元内的瘦素行动是不需要的纠正糖尿病高血糖症的中枢瘦素输注。我们的结论是，在VMN的瘦素信号足以介导瘦素的抗糖尿病作用，但可能不是必要的这种效果。瘦素在分布式神经网络中的作用可能介导其对葡萄糖稳态的影响。
In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.