The Double Life of Irs
| Autor: | Rebecca A. Haeusler, Domenico Accili |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
endocrine system
medicine.medical_specialty Physiology medicine.medical_treatment FOXO1 Article Eating Mice Phosphatidylinositol 3-Kinases Insulin resistance Internal medicine Insulin receptor substrate medicine Animals Homeostasis Insulin Molecular Biology Adaptor Proteins Signal Transducing biology Forkhead Box Protein O1 Intracellular Signaling Peptides and Proteins Forkhead Transcription Factors Lipid metabolism Fasting Cell Biology Lipid Metabolism medicine.disease Phosphoproteins IRS2 IRS1 Insulin receptor Endocrinology Glucose Liver biology.protein Insulin Receptor Substrate Proteins Insulin Resistance hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Cell Metabolism. (1):7-9 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2008.06.010 |
| Popis: | The Forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO-mice). DKO-mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr and Igf1. Liver-specific deletion of Foxo1 in DKO-mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2→PI-3K→Akt→Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth. |
| Databáze: | OpenAIRE |
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