Abstract
Objective:To investigate whether the improvement in hyperglycemia by dietary control influences hyperglycemia-induced pathologies in tissues of juvenile obese (ob/ob) mice.Design:Five-week-old ob/ob mice were fed a very low carbohydrate ketogenic diet (KD) for 7 weeks. The blood glucose levels and body weight were monitored during this period. Biochemical parameters in the serum and tissue pathologies of the mice were analyzed at the end of the 7-week period.Results:The hyperglycemic phenotype of the ob/ob mice was improved by KD feeding for 7 weeks. Surprisingly, we found that KD feeding also drastically reduced the hepatic steatosis phenotype in ob/ob mice, while their obesity phenotype was unaltered. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that several proteins found in the liver of ob/ob mice fed a regular chow diet were undetectable after being fed KD. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) MASCOT search and western blot analysis revealed that the proteins absent from the mice fed KD included fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), which are key enzymes for lipogenesis in the liver. Fatty acid analysis supported the results because the ratio of C18:1, which is a major product of lipogenesis, was reduced by KD feeding. However, C18:2, which cannot be synthesized in mammalian cells but is present in the KD, was found to be a major component in the liver of KD-fed ob/ob mice.Conclusion:Hyperglycemia promotes hepatic steatosis via the lipogenic pathway in the liver of juvenile ob/ob mice. However, the development of steatosis is prevented by feeding KD owing to an improvement in hyperglycemia. We found that the progression of steatosis is reflected by the composition of fatty acids in the total lipids of the liver and serum.
Highlights
Metabolic diseases elicited by chronic hyperglycemia are most often associated with diabetes mellitus
We established a mouse model that improves the hyperglycemic phenotype of ob/ob mice by feeding ketogenic diet (KD) beginning at juvenile stage
We succeeded in preventing the progression of hepatic steatosis by feeding KD, which involves long-term suppression of hyperglycemia
Summary
Metabolic diseases elicited by chronic hyperglycemia are most often associated with diabetes mellitus. Serious chronic hyperglycemia causes several complications such as retinopathy, neuropathy and nephropathy.[1,2] Hyperglycemia is common in various diseases, such as vascular complications, myocardial infraction, cancer and Alzheimer’s disease.[3,4,5,6] a recent study revealed that an excessive quantity of extracellular glucose induces insulin resistance in the cell.[7] This result suggests that hyperglycemia could produce peripheral insulin resistance in vivo. An effective therapy for these diseases remains elusive because of a lack of information on the molecular mechanisms by which hyperglycemia induces peripheral pathologies. A comprehensive approach to understanding hyperglycemiainduced pathologies should be systematically developed in vivo. Such an approach will provide valuable information on these complex problems, which cannot be fully addressed by cell culture-based investigations. The establishment of animal models that reflect the pathological processes is an effective research tool for understanding the developmental mechanisms of these diseases
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