Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR
AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the ro...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-01-01
|
| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319303263 |
| _version_ | 1818994580214775808 |
|---|---|
| author | Tomohito Shibata Akira Takaguri Kazuo Ichihara Kumi Satoh |
| author_facet | Tomohito Shibata Akira Takaguri Kazuo Ichihara Kumi Satoh |
| author_sort | Tomohito Shibata |
| collection | DOAJ |
| description | AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α–induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal–regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α–induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. Taken together, these findings provide evidence that AMPK plays a crucial role in improving of type 2 diabetes. Keywords:: 3T3L1 adipocyte, AICAR, insulin receptor substrate (IRS)-1, DUSP9/MKP-4, insulin resistance |
| first_indexed | 2024-12-20T21:00:12Z |
| format | Article |
| id | doaj.art-9795fceec6c24583b90d51d219dd1ae2 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-20T21:00:12Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-9795fceec6c24583b90d51d219dd1ae22022-12-21T19:26:43ZengElsevierJournal of Pharmacological Sciences1347-86132013-01-01122293102Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICARTomohito Shibata0Akira Takaguri1Kazuo Ichihara2Kumi Satoh3Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, JapanDivision of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, JapanDivision of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, JapanDivision of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, Japan; Corresponding author. kumi@hokuyakudai.ac.jpAMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α–induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal–regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α–induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. Taken together, these findings provide evidence that AMPK plays a crucial role in improving of type 2 diabetes. Keywords:: 3T3L1 adipocyte, AICAR, insulin receptor substrate (IRS)-1, DUSP9/MKP-4, insulin resistancehttp://www.sciencedirect.com/science/article/pii/S1347861319303263 |
| spellingShingle | Tomohito Shibata Akira Takaguri Kazuo Ichihara Kumi Satoh Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR Journal of Pharmacological Sciences |
| title | Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR |
| title_full | Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR |
| title_fullStr | Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR |
| title_full_unstemmed | Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR |
| title_short | Inhibition of the TNF-α–Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR |
| title_sort | inhibition of the tnf α induced serine phosphorylation of irs 1 at 636 639 by aicar |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319303263 |
| work_keys_str_mv | AT tomohitoshibata inhibitionofthetnfainducedserinephosphorylationofirs1at636639byaicar AT akiratakaguri inhibitionofthetnfainducedserinephosphorylationofirs1at636639byaicar AT kazuoichihara inhibitionofthetnfainducedserinephosphorylationofirs1at636639byaicar AT kumisatoh inhibitionofthetnfainducedserinephosphorylationofirs1at636639byaicar |