Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis.
Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis.
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DOI：
10.1016/j.molmet.2017.01.002
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发表时间：
2017-03
影响因子：
8.1
通讯作者：
Scherer PE
中科院分区：
文献类型：
--
作者：
Holland WL;Xia JY;Johnson JA;Sun K;Pearson MJ;Sharma AX;Quittner-Strom E;Tippetts TS;Gordillo R;Scherer PE
脂联素及其同源受体AdipoR1和AdipoR2诱导的信号转导因其促进胰岛素敏感性和抗脂肪变性的能力而受到关注。这些受体的激活促进了神经酰胺的脱酰化，神经酰胺是一种脂代谢产物，似乎在损害胰岛素信号方面发挥了因果作用。在这里，我们已经开发出在四环素反应元件的诱导控制下过表达AdipoR1或AdipoR2的转基因小鼠。这些代表了第一个可诱导的遗传模型，可以在成年小鼠组织中敏锐地操纵脂联素受体信号，使我们能够直接评估AdipoR信号对糖和脂代谢的影响。脂联素受体亚型在脂肪细胞或肝细胞中的过表达足以增强神经酰胺酶活性、全身葡萄糖代谢和肝脏胰岛素敏感性，同时反对肝脏脂肪变性。重要的是，在脂联素基因敲除的背景下，新陈代谢的改善不会发生。当受到2型糖尿病瘦素缺乏遗传模型的挑战时，脂肪或肝脏中的AdipoR2表达足以逆转高血糖和糖耐量异常。这些观察表明，脂联素在AdipoR诱导的神经酰胺酶激活中起关键作用，该酶通过肝脏和脂肪组织鞘磷脂之间的快速“串扰”来增强肝脏的葡萄糖和脂肪代谢。脂肪中的脂联素受体信号对全身的糖脂代谢有促进作用。小分子脂联素受体拮抗剂AdipoRon可降低肝脏神经酰胺。脂肪细胞中神经酰胺的耗尽会导致肝脏神经酰胺的减少。肝细胞中神经酰胺的耗尽会导致脂肪鞘磷脂蓄积减少。脂联素在脂联素受体对葡萄糖、神经酰胺和脂类代谢的有益作用中是必不可少的。
Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids. Adiponectin receptor signaling in adipose prompts beneficial effects on whole-body glucose and lipid metabolism. The small molecule adiponectin receptor antagonist AdipoRon lowers hepatic ceramides. Depletion of ceramides in adipocytes results in diminished hepatic ceramide accumulation. Depletion of ceramides in hepatocytes results in diminished adipose sphingolipid accumulation. Adiponectin is essential for the beneficial effects of adiponectin receptors on glucose, ceramide, and lipid metabolism.