Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Bâtiment Buffon, P. O. box 7126, 4, rue Marie-Andrée Lagroua Weill-Halle, 75205, Paris Cedex 13, France.
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum, Munich, Germany.
Diabetologia. 2017 Jul;60(7):1314-1324. doi: 10.1007/s00125-017-4282-7. Epub 2017 Apr 29.
AIMS/HYPOTHESIS: Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis.
We injected an adeno-associated virus (AAV) expressing Cre-green fluorescent protein into the MBH of Lpl-floxed mice (and wild-type mice) to specifically decrease LPL activity in the MBH. In parallel, we injected an AAV overexpressing Lpl into the MBH of wild-type mice. We then studied energy homeostasis and hypothalamic ceramide content.
The partial deletion of Lpl in the MBH in mice led to an increase in body weight compared with controls (37.72 ± 0.7 g vs 28.46 ± 0.12, p < 0.001) associated with a decrease in locomotor activity. These mice developed hyperinsulinaemia and glucose intolerance. This phenotype also displayed reduced expression of Cers1 in the hypothalamus as well as decreased concentration of several C18 species of ceramides and a 3-fold decrease in total ceramide intensity. Conversely, overexpression of Lpl specifically in the MBH induced a decrease in body weight.
CONCLUSIONS/INTERPRETATION: Our study shows that LPL in the MBH is an important regulator of body weight and glucose homeostasis.
目的/假设：能量平衡的调节涉及许多因素，包括营养素，其中包括循环脂质，作为告知中枢神经系统机体能量状态的外周信号。已经表明，神经元脂蛋白脂肪酶（LPL）通过水解富含三酰基甘油的脂质颗粒参与能量平衡的控制。在这里，我们测试了这样一个假设，即中脑基底核（MBH）中的 LPL-一种已知参与代谢稳态调节的核-也可能有助于体重和葡萄糖稳态的调节。
我们将表达 Cre-绿色荧光蛋白的腺相关病毒（AAV）注射到 Lpl 基因敲除小鼠（和野生型小鼠）的 MBH 中，以特异性降低 MBH 中的 LPL 活性。与此同时，我们将过表达 Lpl 的 AAV 注射到野生型小鼠的 MBH 中。然后，我们研究了能量平衡和下丘脑神经酰胺含量。
与对照组相比，Lpl 在小鼠 MBH 中的部分缺失导致体重增加（37.72±0.7 g 与 28.46±0.12，p<0.001），同时运动活性降低。这些小鼠出现胰岛素血症和葡萄糖不耐受。这种表型还显示下丘脑 Cers1 表达减少，几种 C18 神经酰胺浓度降低，总神经酰胺强度降低 3 倍。相反，Lpl 特异性过表达在 MBH 中诱导体重下降。
结论/解释：我们的研究表明，MBH 中的 LPL 是体重和葡萄糖稳态的重要调节因子。
