GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues.
GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues.
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DOI：
10.1096/fj.201800171r
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Hundal HS
中科院分区：
文献类型：
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作者：
Lipina C;Walsh SK;Mitchell SE;Speakman JR;Wainwright CL;Hundal HS
新的证据表明，G蛋白偶联受体55（GPR 55），内源性大麻素系统的一个非经典受体，L-α-溶血磷脂酰肌醇和各种大麻素配体激活，可以调节内分泌功能和能量代谢。我们研究了GPR 55缺乏和调节如何影响骨骼肌、脂肪组织和肝脏中的胰岛素信号传导，以及与胰岛素作用和能量代谢有关的蛋白质的表达分析。我们发现，GPR 55基因敲除小鼠在这些组织中显示出胰岛素敏感性降低，这可以通过PKB/Akt及其下游靶点的磷酸化减少来证明，同时伴随着相对于野生型小鼠的肥胖增加和体力活动减少。受损的组织胰岛素敏感性与骨骼肌中胰岛素受体底物-1丰度降低相一致，而在肝脏和附睾脂肪中，它与3-磷酸肌醇脂质磷酸酶、磷酸酶和张力蛋白同源物的表达增加相关。相反，GPR 55激活增强了培养的骨骼肌细胞、脂肪细胞和肝细胞中的胰岛素信号传导;受体拮抗剂和L 6肌管中的GPR 55基因沉默否定了这种反应。在3 T3-L1脂肪细胞中持续的GPR 55拮抗作用增强了与脂肪生成有关的蛋白质的表达，并促进了甘油三酯的积累。我们的研究结果将GPR 55确定为胰岛素作用和脂肪形成的正调节剂，并作为对抗肥胖诱导的代谢功能障碍和胰岛素抵抗的潜在治疗靶点。利皮纳角，沃尔什，S. K.，米切尔，S。E、Speakman，J.R.，温赖特角L.，Hundal，H. S. GPR 55缺乏与肥胖增加和外周代谢组织中胰岛素信号传导受损相关。
Emerging evidence indicates that G-protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L-α-lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function and energy metabolism. We examined how GPR55 deficiency and modulation affects insulin signaling in skeletal muscle, adipose tissue, and liver alongside expression analysis of proteins implicated in insulin action and energy metabolism. We show that GPR55-null mice display decreased insulin sensitivity in these tissues, as evidenced by reduced phosphorylation of PKB/Akt and its downstream targets, concomitant with increased adiposity and reduced physical activity relative to wild-type counterparts. Impaired tissue insulin sensitivity coincided with reduced insulin receptor substrate-1 abundance in skeletal muscle, whereas in liver and epididymal fat it was associated with increased expression of the 3-phosphoinoistide lipid phosphatase, phosphatase and tensin homolog. In contrast, GPR55 activation enhanced insulin signaling in cultured skeletal muscle cells, adipocytes, and hepatocytes; this response was negated by receptor antagonists and GPR55 gene silencing in L6 myotubes. Sustained GPR55 antagonism in 3T3-L1 adipocytes enhanced expression of proteins implicated in lipogenesis and promoted triglyceride accumulation. Our findings identify GPR55 as a positive regulator of insulin action and adipogenesis and as a potential therapeutic target for countering obesity-induced metabolic dysfunction and insulin resistance.—Lipina, C., Walsh, S. K., Mitchell, S. E., Speakman, J. R., Wainwright, C. L., Hundal, H. S. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues.