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Sci Rep. 2016 Jul 21;6:30111. doi: 10.1038/srep30111.

Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism.

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Department of Anatomy and Convergence Medical Science, Bio Anti-aging Medical Research Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.
Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea.
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Department of Pathology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
C&K Genomics, Seoul, Republic of Korea.
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea.


Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. (1)H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications.

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