Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia
| Autor: | Joseph A. Baur, Paul M. Titchenell, Niels D. Martin, Carrie Sims, Matthew Gavin, Jamarie Sostre-Colón, Anna E. Garcia Whitlock |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine medicine.medical_specialty FGF21 medicine.medical_treatment Lipolysis Adipose tissue 030209 endocrinology & metabolism FOXO1 Brief Communication Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Stress Physiological Internal medicine medicine Hyperinsulinemia Animals Humans Glucose homeostasis Molecular Biology Mice Knockout biology business.industry Insulin AKT Forkhead Transcription Factors Cell Biology medicine.disease RC31-1245 Stress-induced hyperglycemia Insulin receptor 030104 developmental biology Endocrinology Adipose Tissue Gene Expression Regulation Liver Hyperglycemia biology.protein FOXO business hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Molecular Metabolism, Vol 51, Iss, Pp 101246-(2021) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. Methods We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. Results Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. Conclusions This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress. Highlights • Liver forkhead box O (FOXO) target gene expression is increased in critical illness. • Loss of FOXO1, 3, and 4 in the liver mitigates stress-induced hyperglycemia (SIH). • Hepatic FOXO drives SIH via direct and indirect means in the liver and adipose. |
| Databáze: | OpenAIRE |
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