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Articles by I. Shimomura
Total Records ( 5 ) for I. Shimomura
  H Kobayashi , M Matsuda , A Fukuhara , R Komuro and I. Shimomura
 

Oxidative stress plays an important role in obesity-related metabolic diseases. Glutathione peroxidase (GPX) is an antioxidant enzyme downregulated in adipose tissue of obese mice. However, the role of GPX in adipocytes remains elusive. The objective of this study was to clarify the pathophysiological changes in GPX activity and glutathione metabolism and their roles in the pathogenesis of insulin resistance in adipocytes. To achieve this goal, we measured cellular GPX activity, glutathione (GSH) contents, GSH/GSSG ratio, and mRNA expression of -glutamylcysteine synthetase (-GCS), a rate-limiting enzyme for de novo GSH synthesis, in adipose tissue of control and ob/ob mice and in 3T3-L1 adipocytes treated with insulin, H2O2, free fatty acid (FFA), or TNF. Furthermore, we investigated the effects of GPX inhibition with a specific GPX inhibitor or RNA interference against GPX, H2O2, and reduced GSH on insulin signaling in 3T3-L1 adipocytes. ob/ob Mice showed not only a decrease in cellular activity of GPXs (GPX1, -4, and -7) but also an increase in -GCS expression, resulting in increased GSH contents in adipose tissue. These alterations in glutathione metabolism were also observed during differentiation of 3T3-L1 cells and their exposure to insulin, FFA, or H2O2. Inhibition of GPX activity, addition of GSH, and H2O2 resulted in impaired insulin signaling in 3T3-L1 adipocytes. These results suggest that decreased GPX activity and increased -GCS expression lead to overaccumulation of GSH, which might be involved in the pathogenesis of insulin resistance in obesity.

  T Hibuse , N Maeda , H Nakatsuji , Y Tochino , K Fujita , S Kihara , T Funahashi and I. Shimomura
  Aims

Cardiomyocytes require fatty acids and glucose for energy production. However, other nutrients and substrates that may serve as possible candidates for a cardiac energy source have not been fully studied. Several reports showed that a moderate expression of aquaporin 7 (AQP7), a member of the aquaglyceroporin family that is permeated by glycerol and water, is observed in heart tissue. However, the functional role of cardiac AQP7 is not clear. The aim of this study was to investigate the significance of glycerol as a cardiac energy substrate and to clarify the role of cardiac AQP7.

Methods and results

Heart function and morphology were examined in AQP7-knockout (KO) mice under basal conditions and during pressure overload [isoproterenol infusion and transverse aortic constriction (TAC)]. Glycerol uptake and glycerol-dependent ATP production were measured in AQP7-knockdown cardiac cells. Cardiac glycerol consumption was analysed in ex vivo beating hearts. Cardiac morphology and function in KO mice were similar to those of wild-type (WT) mice under basal conditions, although low glycerol and ATP content were noted in hearts of KO mice. In H9c2 cardiomyotubes, knockdown of AQP7 was associated with a significant reduction of glycerol uptake. The ex vivo heart study demonstrated that cardiac glycerol consumption levels in KO mice were significantly lower than those of WT mice. Furthermore, isoproterenol challenge induced severe left ventricular hypertrophy in KO mice, and TAC resulted in a higher mortality rate in KO mice than in WT mice.

Conclusion

The results indicate that AQP7 acts as a glycerol facilitator in cardiomyocytes and that glycerol is a substrate for cardiac energy production.

 
 
 
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