Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia.
Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia.
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DOI：
10.1371/journal.pone.0055963
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cani PD
中科院分区：
文献类型：
--
作者：
Geurts L;Muccioli GG;Delzenne NM;Cani PD
肥胖和2型糖尿病的特征在于低度炎症、代谢性内毒素血症（即，增加的血浆脂多糖[LPS]水平）和改变的内源性大麻素（eCB）-系统张力。本研究的目的是解读eCB系统刺激或代谢性内毒素血症在葡萄糖耐受不良、代谢性炎症和脂质代谢改变发作中的特定作用。使用皮下微型泵用大麻素（CB）受体激动剂（HU 210）或低剂量LPS处理小鼠6周。在对照（CT）饮食下处理3周后，在接下来的3周时间内用高脂肪（HF）饮食攻击每组小鼠的一半。在基础条件（对照饮食）下，慢性CB受体激动剂处理（即，6周）诱导葡萄糖耐受不良，刺激代谢性内毒素血症，并增加肌肉中的巨噬细胞浸润（CD 11 c和F4/80表达）;该现象与该组织中脂质代谢改变（PGC-1α表达增加和CPT-1b表达降低）相关。长期LPS治疗倾向于增加体重和脂肪量，对其他代谢参数的影响较小。在用CB激动剂预处理后用HF饮食喂养小鼠加重了HF饮食诱导的葡萄糖耐受不良、肌肉巨噬细胞浸润和肌肉的脂质含量，而不影响体重或脂肪量。基础条件下的慢性CB受体刺激诱导葡萄糖耐受不良，刺激代谢性炎症并改变肌肉中的脂质代谢。这些影响在同时摄入HF饮食后恶化。在这里，我们强调了eCB系统和LPS在肥胖和2型糖尿病的几个标志的病理生理学中所起的核心作用。
Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT) diet, one-half of each group of mice were challenged with a high fat (HF) diet for the following 3-week period. Under basal conditions (control diet), chronic CB receptor agonist treatment (i.e., 6 weeks) induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression) in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression) in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle's lipid content without affecting the body weight or the fat mass. Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.
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