Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.
Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.
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孤儿 GPR116 介导脂肪组织中肝因子 FNDC4 的胰岛素增敏作用。
DOI：
10.1038/s41467-021-22579-1
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发表时间：
2021-05-20
影响因子：
16.6
通讯作者：
Herzig S
中科院分区：
文献类型：
--
作者：
Georgiadi A;Lopez-Salazar V;Merahbi RE;Karikari RA;Ma X;Mourão A;Klepac K;Bühler L;Alfaro AJ;Kaczmarek I;Linford A;Bosma M;Shilkova O;Ritvos O;Nakamura N;Hirose S;Lassi M;Teperino R;Machado J;Scheideler M;Dietrich A;Geerlof A;Feuchtinger A;Blutke A;Fischer K;Müller TD;Kessler K;Schöneberg T;Thor D;Hornemann S;Kruse M;Nawroth P;Pivovarova-Ramich O;Pfeiffer AFH;Sattler M;Blüher M;Herzig S
不同组织之间的适当功能相互作用是全身代谢控制的关键组成部分。事实上，内分泌组织间通讯的中断是肥胖症和糖尿病中严重代谢功能障碍的标志。在这里，我们表明，FNDC 4-GPR 116，肝脏白色脂肪组织内分泌轴控制葡萄糖稳态。我们发现肝脏主要控制可溶性FNDC 4（sFNDC 4）的循环水平，肝细胞因子FNDC 4的降低导致小鼠糖尿病前期。此外，我们鉴定了孤儿粘附GPCR GPR 116作为白色脂肪组织中sFNDC 4的受体。在sFNDC 4与GPR 116直接和高亲和力结合后，sFNDC 4促进白色脂肪细胞中的胰岛素信号传导和胰岛素介导的葡萄糖摄取。事实上，在糖尿病前期小鼠中补充FcsFNDC 4以白脂肪细胞选择性和GPR 116依赖性方式改善了葡萄糖耐量和炎症标志物。值得注意的是，sFNDC 4-GPR 116，肝脏-脂肪组织轴在（前）糖尿病人类患者中被抑制。因此，我们的研究结果现在将允许利用这种内分泌回路作为肥胖相关的糖尿病前期的替代治疗策略。可溶性生物活性形式的跨膜蛋白纤连蛋白III型结构域包含4（sFNDC 4）具有抗炎作用并改善胰岛素敏感性。在这里，作者表明，肝脏来源的sFNDC 4通过脂肪组织GPCR GPR 116发出信号，以促进胰岛素介导的葡萄糖摄取。
The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes. The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.
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影响因子：
4.6
作者：
Knierim, Alexander Bernd;Roethe, Juliane;Schoeneberg, Torsten
通讯作者：
Schoeneberg, Torsten
影响因子：
16.6
作者：
Bosma M;Gerling M;Pasto J;Georgiadi A;Graham E;Shilkova O;Iwata Y;Almer S;Söderman J;Toftgård R;Wermeling F;Boström EA;Boström PA
通讯作者：
Boström PA
影响因子：
8.2
作者：
Kannt, Aimo;Pfenninger, Anja;Teichert, Lenore;Toenjes, Anke;Dietrich, Arne;Schon, Michael R.;Kloeting, Nora;Blueher, Matthias
通讯作者：
Blueher, Matthias
影响因子：
4.8
作者：
Kane, S;Sano, H;Lienhard, GE
通讯作者：
Lienhard, GE
影响因子：
6.9
作者：
Guiu-Jurado, Esther;Unthan, Mark;Blueher, Matthias
通讯作者：
Blueher, Matthias