The Stress-Responsive microRNA-34a Alters Insulin Signaling and Actions in Adipocytes through Induction of the Tyrosine Phosphatase PTP1B.
The Stress-Responsive microRNA-34a Alters Insulin Signaling and Actions in Adipocytes through Induction of the Tyrosine Phosphatase PTP1B.
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DOI：
10.3390/cells11162581
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发表时间：
2022-08-19
期刊：
影响因子：
6
通讯作者：
Cormont, Mireille
中科院分区：
文献类型：
--
作者：
Cornejo, Pierre-Jean;Vergoni, Bastien;Ohanna, Mickael;Angot, Brice;Gonzalez, Teresa;Jager, Jennifer;Tanti, Jean-Francois;Cormont, Mireille
肥胖期间，代谢应激会改变脂肪细胞中胰岛素的信号传导和作用，但分子联系仍不完全清楚。 microRNA-34（miR-34家族的成员在应激反应中发挥着关键作用，之前的研究表明肥胖期间脂肪组织中miR-34a上调。在这里，我们将miR-34a鉴定为脂肪细胞胰岛素抵抗的新介质。我们证实了肥胖小鼠脂肪组织中miR-34a的上调，这种上调仅在脂肪细胞部分中观察到。miR-34a在肥胖小鼠中的过表达3T3-L1 脂肪细胞或瘦小鼠的脂肪垫显着降低了胰岛素引起的 Akt 激活和胰岛素诱导的葡萄糖转运，同时伴随着 miR-34a 靶标 VAMP2 的表达减少以及酪氨酸磷酸酶 PTP1B 的表达增加。重要的是，PTP1B 沉默阻止了 miR-34a 对胰岛素信号传导的抑制作用。通过抑制 Naprt 和 Nampt，导致 Sirtuin-1 的抑制，从而促进 PTP1B 的上调。此外，肥胖小鼠脂肪组织中 Nampt 和 Naprt 的 mRNA 表达降低。总的来说，我们的结果确定 miR-34a 是脂肪细胞中胰岛素信号传导的新抑制剂，为对抗胰岛素抵抗提供了潜在的途径。
Metabolic stresses alter the signaling and actions of insulin in adipocytes during obesity, but the molecular links remain incompletely understood. Members of the microRNA-34 (miR-34 family play a pivotal role in stress response, and previous studies showed an upregulation of miR-34a in adipose tissue during obesity. Here, we identified miR-34a as a new mediator of adipocyte insulin resistance. We confirmed the upregulation of miR-34a in adipose tissues of obese mice, which was observed in the adipocyte fraction exclusively. Overexpression of miR-34a in 3T3-L1 adipocytes or in fat pads of lean mice markedly reduced Akt activation by insulin and the insulin-induced glucose transport. This was accompanied by a decreased expression of VAMP2, a target of miR-34a, and an increased expression of the tyrosine phosphatase PTP1B. Importantly, PTP1B silencing prevented the inhibitory effect of miR-34a on insulin signaling. Mechanistically, miR-34a decreased the NAD+ level through inhibition of Naprt and Nampt, resulting in an inhibition of Sirtuin-1, which promoted an upregulation of PTP1B. Furthermore, the mRNA expression of Nampt and Naprt was decreased in adipose tissue of obese mice. Collectively, our results identify miR-34a as a new inhibitor of insulin signaling in adipocytes, providing a potential pathway to target to fight insulin resistance.
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影响因子：
7.7
作者：
Delibegovic M;Zimmer D;Kauffman C;Rak K;Hong EG;Cho YR;Kim JK;Kahn BB;Neel BG;Bence KK
通讯作者：
Bence KK
影响因子：
6
作者：
Gharanei S;Shabir K;Brown JE;Weickert MO;Barber TM;Kyrou I;Randeva HS
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Randeva HS
脂肪组织 microRNA 作为人类肥胖中 CCL2 产生的调节因子。
影响因子：
7.7
作者：
Arner E;Mejhert N;Kulyté A;Balwierz PJ;Pachkov M;Cormont M;Lorente-Cebrián S;Ehrlund A;Laurencikiene J;Hedén P;Dahlman-Wright K;Tanti JF;Hayashizaki Y;Rydén M;Dahlman I;van Nimwegen E;Daub CO;Arner P
通讯作者：
Arner P
影响因子：
4.6
作者：
Isik M;Blackwell TK;Berezikov E
通讯作者：
Berezikov E
影响因子：
5.3
作者：
Fu, Ting;Seok, Sunmi;Kemper, Jongsook Kim
通讯作者：
Kemper, Jongsook Kim