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Published on: November 16, 2011
Irs1 serine 307 promotes insulin sensitivity in mice
Kyle D Copps1, Nancy J Hancer, Lynn Opare-Ado
1Children's Hospital Boston, Harvard Medical School, MA 02115, USA.
Cell Metabolism
|January 16, 2010
Summary
Contrary to expectations, serine phosphorylation of insulin receptor substrates (IRS) actually improves insulin signaling. This finding challenges previous research, suggesting a positive regulatory role in managing insulin resistance.
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Endocrinology
Background:
- Serine phosphorylation of insulin receptor substrates (IRS) is widely believed to induce insulin resistance.
- Specifically, Ser307 in rodent IRS1 is a key site implicated in mediating this effect.
Purpose of the Study:
- To investigate the in vivo role of Ser307 phosphorylation in regulating insulin signaling and resistance.
- To determine if Ser307 acts as a negative regulator of IRS1 function.
Main Methods:
- Generation of knockin mice with Ser307 (human Ser312) mutated to alanine (A/A).
- High-fat diet and chow feeding studies in wild-type and genetically modified mice.
- Analysis of insulin signaling in liver and muscle tissues, including ex vivo hepatocyte studies.
- Adenovirus-mediated delivery of mutant IRS1 in mice lacking hepatic IRS1 and IRS2.
Main Results:
- A/A mice on a high-fat diet exhibited exacerbated insulin resistance, with impaired muscle insulin signaling and enhanced pancreatic compensation.
- Mice lacking IRS2 and carrying the Ser307 alanine mutation (A/lox::LKO2) showed profound insulin resistance and impaired hepatic insulin signaling.
- Mutant A307 IRS1 partially restored insulin response in mice lacking hepatic IRS1 and IRS2, indicating a role in maintaining signaling.
Conclusions:
- Contrary to cell-based studies, Ser307 in mice functions as a positive regulatory site for IRS1.
- This site moderates insulin resistance severity by preserving proximal insulin signaling pathways.
- The findings necessitate a re-evaluation of serine phosphorylation's role in insulin resistance.
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