PMID- 27439777 OWN - NLM STAT- MEDLINE DCOM- 20180502 LR - 20181113 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 6 DP - 2016 Jul 21 TI - Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. PG - 30111 LID - 10.1038/srep30111 [doi] LID - 30111 AB - 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. FAU - Kim, Kyung Eun AU - Kim KE AD - 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. FAU - Jung, Youngae AU - Jung Y AD - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea. FAU - Min, Soonki AU - Min S AD - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea. AD - Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea. FAU - Nam, Miso AU - Nam M AD - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea. AD - Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea. FAU - Heo, Rok Won AU - Heo RW AD - 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. FAU - Jeon, Byeong Tak AU - Jeon BT AD - Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. FAU - Song, Dae Hyun AU - Song DH AD - Department of Pathology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea. FAU - Yi, Chin-Ok AU - Yi CO AD - 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. FAU - Jeong, Eun Ae AU - Jeong EA AD - 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. FAU - Kim, Hwajin AU - Kim H AD - 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. FAU - Kim, Jeonghyun AU - Kim J AD - Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea. FAU - Jeong, Seon-Yong AU - Jeong SY AD - Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea. FAU - Kwak, Woori AU - Kwak W AD - C&K Genomics, Seoul, Republic of Korea. FAU - Ryu, Do Hyun AU - Ryu do H AD - Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea. FAU - Horvath, Tamas L AU - Horvath TL AD - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. FAU - Roh, Gu Seob AU - Roh GS AD - 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. AD - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. FAU - Hwang, Geum-Sook AU - Hwang GS AD - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea. AD - Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea. LA - eng GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160721 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Ketones) RN - 0 (Triglycerides) RN - 9007-34-5 (Collagen) SB - IM MH - Animals MH - *Body Weight MH - *Caloric Restriction MH - Chromatography, Liquid MH - Collagen/metabolism MH - Endoplasmic Reticulum Stress MH - Ketones/metabolism MH - Lipid Metabolism MH - Lipogenesis MH - Liver/*metabolism MH - Mass Spectrometry MH - Metabolomics MH - Mice MH - Non-alcoholic Fatty Liver Disease/*diet therapy/metabolism MH - Proton Magnetic Resonance Spectroscopy MH - Triglycerides/biosynthesis PMC - PMC4954985 EDAT- 2016/07/22 06:00 MHDA- 2018/05/03 06:00 PMCR- 2016/07/21 CRDT- 2016/07/22 06:00 PHST- 2016/03/17 00:00 [received] PHST- 2016/06/27 00:00 [accepted] PHST- 2016/07/22 06:00 [entrez] PHST- 2016/07/22 06:00 [pubmed] PHST- 2018/05/03 06:00 [medline] PHST- 2016/07/21 00:00 [pmc-release] AID - srep30111 [pii] AID - 10.1038/srep30111 [doi] PST - epublish SO - Sci Rep. 2016 Jul 21;6:30111. doi: 10.1038/srep30111.