posted on 2020-07-09, 13:48authored byAda AdminAda Admin, Luyao Zhang, Xue Li, Nan Zhang, Xin Yang, Tianyun Hou, Wan Fu, Fengjie Yuan, Lina Wang, He Wen, Yuan Tian, Hongquan Zhang, Xifeng Lu, Wei-Guo Zhu
Endosomes
help activate the hepatic insulin-evoked Akt signaling pathway, but the
underlying regulatory mechanisms are unclear. Previous studies have suggested
that the endosome located protein WD Repeat and FYVE Domain Containing 2
(WDFY2) might be involved in metabolic disorders, such as diabetes. Here, we
generated Wdfy2 knockout (KO) mice
and assessed the metabolic consequences. These KO mice exhibited systemic
insulin resistance, with increased gluconeogenesis and suppressed glycogen
accumulation in the liver. Mechanistically, we found that the insulin-stimulated
activation of Akt2 and its substrates FoxO1 and GSK-3β, is attenuated in the Wdfy2 KO liver and H2.35 hepatocytes,
suggesting that WDFY2 acts as an important regulator of hepatic Akt2 signaling.
We further found that WDFY2 interacts with the insulin receptor (INSR) via its
WD1-4 domain and localizes the INSR to endosomes after insulin stimulation.
This process ensures that the downstream insulin receptor substrates 1 and 2
(IRS1/2) can be recruited to the endosomal INSR. IRS1/2–INSR binding promotes
IRS1/2 phosphorylation and subsequent activation, initiating downstream Akt2
signaling in the liver. Interestingly, adeno-associated viral WDFY2 delivery
ameliorated metabolic defects in db/db
mice. These findings demonstrate that WDFY2 activates insulin-evoked Akt2
signaling by controlling
endosomal localization of the insulin receptor and IRS1/2 in hepatocytes. This
pathway might constitute a new potential target for diabetes prevention and/or
treatment.
Funding
This work was supported by grants from National Key R&D Program of China [2017YFA0503900]; National Natural Science Foundation of China [81720108027, 81530074]; Science and Technology Program of Guangdong Province in China [2017B030301016]; Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20170818092450901]; Discipline Construction Funding of Shenzhen [(2016)1452]; Open Funding of Shenzhen Bay Laboratory [SZBL2019062801011].