Horakova, O.* ; Medrikova, D.* ; van Schothorst, E.M.* ; Bunschoten, A.* ; Flachs, P.* ; Kus, V.* ; Kuda, O.* ; Bardova, K.* ; Janovska, P.* ; Hensler, M.* ; Rossmeisl, M.* ; Wang-Sattler, R. ; Prehn, C. ; Adamski, J. ; Illig, T. ; Keijer, J.* ; Kopecky, J.*
     
    
        
Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice.
    
    
        
    
    
        
        PLoS ONE 7:e43764 (2012)
    
    
    
      
      
	
	    Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.
	
	
	    
	
       
      
	
	    
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        Publication type
        Article: Journal article
    
 
    
        Document type
        Scientific Article
    
 
    
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        Keywords
        POLYUNSATURATED FATTY-ACIDS; IMPAIRED GLUCOSE-TOLERANCE; INDUCED INSULIN-RESISTANCE; TYPE-2 DIABETES-MELLITUS; ACTIVATED-RECEPTOR-ALPHA; FISH-OIL; WEIGHT-LOSS; MARINE ORIGIN; EICOSAPENTAENOIC ACID; CERAMIDASE ACTIVITY
    
 
    
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        Language
        english
    
 
    
        Publication Year
        2012
    
 
    
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        2012
    
 
    
    
        ISSN (print) / ISBN
        1932-6203
    
 
    
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	    Volume: 7,  
	    Issue: 8,  
	    Pages: ,  
	    Article Number: e43764 
	    Supplement: ,  
	
    
 
    
        
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            Publisher
            Public Library of Science (PLoS)
        
 
        
            Publishing Place
            Lawrence, Kan.
        
 
	
        
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        Reviewing status
        Peer reviewed
    
 
     
    
        POF-Topic(s)
        30201 - Metabolic Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
    
 
    
        Research field(s)
        Genetics and Epidemiology
    
 
    
        PSP Element(s)
        G-505600-001
G-504200-003
G-501900-061
    
 
    
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        Erfassungsdatum
        2012-10-04