Objective

The inability of leptin to suppress food intake in diet-induced obesity, sometimes referred to as leptin resistance, is associated with several distinct pathological hallmarks. One prevailing theory is that impaired transport of leptin across the blood–brain barrier (BBB) represents a molecular mechanism that triggers this phenomenon. Recent evidence, however, has challenged this notion, suggesting that leptin BBB transport is acquired during leptin resistance.

Methods

To resolve this debate, we utilized a novel cerebral Open Flow Microperfusion (cOFM) method to examine leptin BBB transport in male C57BL/6J mice, fed a chow diet or high fat diet (HFD) for 20 days.

Results

Basal plasma leptin levels were 3.8-fold higher in HFD-fed mice (p < 0.05). Leptin administration (2.5 mg/kg) elicited similar pharmacokinetic profiles of circulating leptin. However, while leptin reduced food intake by 20% over 22 h in chow-fed mice, it did not affect food intake in HFD-fed mice. In spite of this striking functional difference, hypothalamic leptin levels, as measured by cOFM, did not differ between chow-fed mice and HFD-fed mice following leptin administration.

Conclusions

These data suggest that leptin transport across the BBB is not impaired in non-obese leptin resistant mice and thus unlikely to play a direct role in the progression of pharmacological leptin resistance.

中文翻译：

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时间分辨的下丘脑开流微灌注显示瘦素抵抗小鼠中正常的瘦素转运穿过血脑屏障。

目的

瘦素不能抑制饮食引起的肥胖症中的食物摄入，有时被称为瘦素抵抗性，与几种不同的病理学特征有关。一种流行的理论是，瘦蛋白跨血脑屏障（BBB）的运输障碍是触发这种现象的分子机制。但是，最近的证据对这一观点提出了挑战，表明在瘦素抵抗过程中获得了瘦素BBB转运。

方法

为了解决这一争论，我们利用一种新颖的脑开放流微灌流（cOFM）方法检查了以普通饮食或高脂饮食（HFD）喂养20天的雄性C57BL / 6J小鼠的瘦素BBB转运。

结果

饲喂HFD的小鼠的基础血浆瘦素水平高3.8倍（p <0.05）。瘦素给药（2.5 mg / kg）引起循环瘦素的相似药代动力学特征。然而，尽管瘦素在以f喂食的小鼠中在22小时内减少了20％的食物摄入量，但它并未影响以HFD喂食的小鼠的食物摄入量。尽管存在这种显着的功能差异，但通过瘦素给药后，通过cOFM测量的下丘脑瘦素水平在食物喂养的小鼠和HFD喂养的小鼠之间没有差异。

结论

这些数据表明，在非肥胖瘦素抗性小鼠中，瘦素跨BBB的运输不会受到损害，因此不可能在药理学瘦素抗性的进展中发挥直接作用。