Document Detail

Acute exercise reduces hepatic glucose production through inhibition of the Foxo1/HNF-4alpha pathway in insulin resistant mice.
MedLine Citation:
PMID:  20421289     Owner:  NLM     Status:  MEDLINE    
Protein hepatocyte nuclear factor 4alpha (HNF-4alpha) is atypically activated in the liver of diabetic rodents and contributes to hepatic glucose production. HNF-4alpha and Foxo1 can physically interact with each other and represent an important signal transduction pathway that regulates the synthesis of glucose in the liver. Foxo1 and HNF-4alpha interact with their own binding sites in the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) promoters, and this binding is required for their effects on those promoters. However, the effect of physical activity on the HNF-4alpha/Foxo1 pathway is currently unknown. Here, we investigate the protein levels of HNF-4alpha and the HNF-4alpha/Foxo1 pathway in the liver of leptin-deficient (ob/ob) and diet-induced obese Swiss (DIO) mice after acute exercise. The ob/ob and DIO mice swam for four 30 min periods, with 5 min rest intervals for a total swimming time of 2h. Eight hours after the acute exercise protocol, the mice were submitted to an insulin tolerance test (ITT) and determination of biochemical and molecular parameters. Acute exercise improved insulin signalling, increasing insulin-stimulated Akt and Foxo1 phosphorylation and decreasing HNF-4alpha protein levels in the liver of DIO and ob/ob mice under fasting conditions. These phenomena were accompanied by a reduction in the expression of gluconeogenesis genes, such as PEPCK and G6Pase. Importantly, the PI3K inhibitor LY292004 reversed the acute effect of exercise on fasting hyperglycaemia, confirming the involvement of the PI3K pathway. The present study shows that exercise acutely improves the action of insulin in the liver of animal models of obesity and diabetes, resulting in increased phosphorylation and nuclear exclusion of Foxo1, and a reduction in the Foxo1/HNF-4alpha pathway. Since nuclear localization and the association of these proteins is involved in the activation of PEPCK and G6Pase, we believe that the regulation of Foxo1 and HNF-4alpha activities are important mechanisms involved in exercise-induced improvement of glucose homeostasis in insulin resistant states.
Cláudio T De Souza; Marisa J S Frederico; Gabrielle da Luz; Dennys E Cintra; Eduardo R Ropelle; José R Pauli; Lício A Velloso
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-04-26
Journal Detail:
Title:  The Journal of physiology     Volume:  588     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-10-04     Revised Date:  2011-08-01    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  2239-53     Citation Subset:  IM    
Exercise Biochemistry and Physiology Laboratory, Postgraduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina - Criciăúma, SC, Brazil.
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MeSH Terms
Active Transport, Cell Nucleus
Diabetes Mellitus / genetics,  metabolism*,  physiopathology
Disease Models, Animal
Forkhead Transcription Factors / metabolism*
Glucose / metabolism*
Glucose Clamp Technique
Glucose-6-Phosphatase / metabolism
Glycogen / metabolism
Hepatocyte Nuclear Factor 4 / metabolism*
Insulin / metabolism*
Insulin Resistance* / genetics
Liver / drug effects,  metabolism*,  physiopathology
Obesity / genetics,  metabolism*,  physiopathology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism
Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
Physical Exertion*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Reg. No./Substance:
0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Hepatocyte Nuclear Factor 4; 0/Hnf4a protein, mouse; 0/Protein Kinase Inhibitors; 11061-68-0/Insulin; 50-99-7/Glucose; 9005-79-2/Glycogen; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt; EC; EC Carboxykinase (GTP)
Comment In:
J Physiol. 2010 Aug 1;588(Pt 15):2687-8   [PMID:  20675815 ]

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