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Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through
Sumit Bhattacharyya1, Leo Feferman1, Joanne K Tobacman2
1From the Department of Medicine, University of Illinois at Chicago and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
The Journal of Biological Chemistry
|March 19, 2015
Summary
Carrageenan food additive causes insulin resistance via inflammation and increased GRB10 protein, disrupting insulin signaling pathways. Targeting these mechanisms may restore insulin sensitivity.
Area of Science:
- Metabolic diseases
- Molecular biology
- Cellular signaling
Background:
- Carrageenan, a common food additive, induces inflammation linked to insulin resistance.
- Inflammation increases Ser(P)(307)-insulin receptor substrate 1 (IRS1), impairing insulin signaling.
- The precise mechanisms causing reduced Ser(P)(473)-AKT in carrageenan-induced insulin resistance require further elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which carrageenan induces insulin resistance.
- To identify additional pathways contributing to the decline in insulin signaling beyond inflammation-induced IRS1 phosphorylation.
- To explore the role of GRB10 protein in carrageenan-mediated insulin resistance.
Main Methods:
- Studies were conducted in human HepG2 cells and C57BL/6J mice.
- Carrageenan exposure was used to induce inflammation and insulin resistance.
- GRB10 silencing, BCL10 silencing, and Tempol (ROS inhibitor) were employed.
- GATA2 activation and its correlation with AKT and GRB10 phosphorylation were analyzed.
- PI3K inhibitor LY294002 was used to assess AKT's role in GATA2 and GRB10 regulation.
Main Results:
- Carrageenan increased GRB10 expression, which inhibits insulin receptor signaling.
- GRB10 silencing partially reversed the decline in Ser(P)(473)-AKT and blocked IRS1 Tyr(P) reduction.
- Combined GRB10 silencing, BCL10 silencing, and Tempol treatment fully restored Ser(P)(473)-AKT levels.
- Carrageenan enhanced GRB10 promoter activity via GATA2 activation.
- AKT phosphorylation positively correlated with GATA2 phosphorylation and GRB10 expression.
Conclusions:
- Carrageenan impairs insulin signaling through inflammation-induced Ser(P)(307)-IRS1 and increased GRB10 expression.
- GRB10 acts transcriptionally, inhibiting IRS1 and contributing to insulin resistance.
- A feedback loop involving AKT, GATA2, and GRB10 modulates insulin responsiveness, linking IRS1 serine and tyrosine phosphorylation.
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