Inhibition of the TNF-α^|^ndash;Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR
Open accessAbstract
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.
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TNF-α affects insulin signaling by phosphorylation of serine in IRS-1 through activation of several serine kinases, including JNK and ERK, which inhibits insulin-induced tyrosine phosphorylation of IRS-1 and downregulates PI3K activity.
“TNF-α affects insulin signaling by phosphorylation of serine in IRS-1 through activation of several serine kinases, including c-Jun-NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which inhibits insulin-induced tyrosine phosphorylation of IRS-1 and downregulates PI3K activity [49].”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [49]
TNF-α causes decreased GLUT-4 expression and decreased glucose transport into cells.
“It causes decreased GLUT-4 expression and decreased glucose transport into cells (Figure 2).”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [49]
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5-aminoimidazole-4-carboxamide ribonucleoside
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- Authors
- Shibata, T., Takaguri, A., Ichihara, K., & Satoh, K.
- Affiliations
- Hokkaido Pharmaceutical University (JP)
- ORCID
- Satoh, Kumi
- Venue
- Journal of Pharmacological Sciences
- Publisher
- Japanese Pharmacological Society
- Published
- 2013
- Volume
- 122
- Issue
- 2
- Pages
- 93-102
- ISSN
- 1347-8613 (ISSN-L)
- 1347-8648
- OpenAlex
- W2014433009
- Cited by
- 28
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 3
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- AMPK, AICAR, IRS-1, serine phosphorylation, TNF-α, ERK1/2 phosphorylation, MAP kinase phosphatase, insulin signaling, adipocytes, type 2 diabetes, db/db mice, blood glucose
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Hypoglycemic Agents, Injections, Intraperitoneal, Insulin Resistance, Mice, Inbred Strains, Phosphorylation, Ribonucleotides, Serine, Stimulation, Chemical, Tumor Necrosis Factor-alpha, Signal Transduction, 3T3-L1 Cells, Extracellular Signal-Regulated MAP Kinases, Mice, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases, AMP-Activated Protein Kinases, Insulin Receptor Substrate Proteins
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