Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages
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DOI：
10.1172/jci83626
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发表时间：
2017-11-01
影响因子：
15.9
通讯作者：
Lutz, Beat
中科院分区：
文献类型：
--
作者：
de Azua, Inigo Ruiz;Mancini, Giacomo;Lutz, Beat
脂肪细胞生理失调导致能量储存不平衡、肥胖和相关疾病，给当前的医疗保健带来了昂贵的负担。大麻素受体1型（Cannabinoid receptor type-1, CB1）通过中枢和外周机制在控制能量代谢中发挥重要作用。在这项工作中，脂肪细胞特异性诱导CB1基因的缺失（Ati-CB1-KO）足以保护成年小鼠免受饮食诱导的肥胖和相关的代谢改变，并逆转已经肥胖的小鼠的表型。与对照组相比，anti - cb1 - ko小鼠表现出体重下降，总脂肪减少，胰岛素敏感性改善，能量消耗增加，脂肪库特异性细胞重构，能量储存能力降低，白色脂肪细胞褐变。这些变化与脂肪组织中交替激活的巨噬细胞的增加以及交感神经张力的增强有关。值得注意的是，这些改变先于体重差异的出现，强调了CB1缺失与触发脂肪组织代谢重编程之间的因果关系。最后，在热中性条件下，anti - cb1 - ko小鼠的瘦表型和脂肪组织中选择性活化巨噬细胞的增加也存在。我们的数据为脂肪细胞、免疫细胞和交感神经系统（SNS）之间的串扰提供了令人信服的证据，其中CB1起着关键的调节作用。
Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.