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

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          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. 1H-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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          Most cited references 51

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          Autophagy regulates lipid metabolism.

          The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
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            Inflammation, stress, and diabetes.

            Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.
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              Caloric restriction delays disease onset and mortality in rhesus monkeys.

              Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

                Author and article information

                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                21 July 2016
                : 6
                [1 ]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
                [2 ]Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute , Seoul, Republic of Korea
                [3 ]Department of Chemistry, Sungkyunkwan University , Suwon, Republic of Korea
                [4 ]Department of Biochemistry, University of Nebraska-Lincoln , Lincoln, NE 68588, USA
                [5 ]Department of Pathology, Institute of Health Sciences, Gyeongsang National University School of Medicine , Jinju, Republic of Korea
                [6 ]Department of Medical Genetics, Ajou University School of Medicine , Suwon, Republic of Korea
                [7 ]C&K Genomics , Seoul, Republic of Korea
                [8 ]Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine , New Haven, CT 06520, USA
                [9 ]Department of Chemistry and Nano Science, Ewha Womans University , Seoul, Republic of Korea
                Author notes

                These authors contributed equally to this work.

                Copyright © 2016, The Author(s)

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