Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Nguyen, Dan J.M.; Samson, Susan L.; Reddy, Varun; Gonzalez, Erica; Sekhar, Rajagopal V.

doi:10.1111/acel.12073

Cited by 81 publications

(83 citation statements)

References 46 publications

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“…Therefore, reduced ROS levels would likely be protective against diet‐induced and aging‐associated insulin resistance in Nmnat3 Tg mice. In accordance with the roles of NAD as a coenzyme in mitochondrial fatty acid oxidation, we observed the preferential use of fatty acids as an energy source in Nmnat3 Tg mice, and such shifts from carbohydrate‐ to fatty acid‐based energy production have been considered metabolically favorable during aging (Nguyen, Samson, Reddy, Gonzalez, & Sekhar, 2013; Schonfeld, Wieckowski, Lebiedzinska, & Wojtczak, 2010; Tucker & Turcotte, 2002). In addition, reduced capacity for fatty acid oxidation is related to insulin resistance (Kelley, Goodpaster, Wing, & Simoneau, 1999).…”

Section: Discussionsupporting

confidence: 77%

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

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SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

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Section: Discussionsupporting

confidence: 77%

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

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“…The current field of aging‐related research is focused more on extending a healthful lifespan, rather than simply extending lifespan, as older individuals with complications of aging that impair the quality of life often do not feel that further extension of lifespan is desirable. It was therefore important to determine whether these mice were also protected from risk factors that impair healthful aging, for example, protection against obesity (American Diabetes, 2004; Brown, Fujioka, Wilson & Woodworth, 2009; Guh et al., 2009) and impaired metabolism (Finkel, 2015; Nguyen, Samson, Reddy, Gonzalez & Sekhar, 2013; Roberts & Rosenberg, 2006). Indeed, the RGS14 KO mice have a reduced WAT/body weight ratio, are protected against the cold, and have increased mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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“…Based on accumulation evidence, excess lipid accumulation promotes lipotoxicity and may induce hepatic injury and inflammation in mice by generating oxidative stress [19, 20]. In addition, oxidative stress participates in the inflammatory response to liver disease in a variety of human conditions and experimental animal models [21, 22].…”

Section: Discussionmentioning

confidence: 99%

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

Chen

Huang

et al. 2017

Cell Physiol Biochem

106

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Background/Aims: Dairy cows with ketosis are characterized by oxidative stress and hepatic damage. The aim of this study was to investigate hepatic oxidative stress and the apoptotic status of ketotic cows, as well as the underlying apoptosis pathway. Methods: The blood aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH) and gamma-glutamyl transferase (GGT) activities and the haptoglobin (HP), serum amyloid A (SAA) and serum apoptotic cytokeratin 18 neo-epitope M30 (CK18 M30) concentrations were determined by commercially available kits and ELISA kits, respectively. Liver histology, TUNEL and Oil red O staining were performed in liver tissue samples. TG contents were measured using an enzymatic kit; Caspase 3 assays were carried out using the Caspase 3 activity assay kit; oxidation and antioxidant markers were measured using biochemical kits; apoptosis pathway were determined by qRT-PCR and western blot. Results: Ketotic cows displayed hepatic fat accumulation. The hepatic malondialdehyde (MDA) content was significantly increased, but the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were markedly decreased in ketotic cows compared with control cows, indicating that ketotic cows displayed severe oxidative stress. Significantly higher serum levels of the hepatic damage markers AST, ALT, GGT and GLDH were observed in ketotic cows than in control cows. The blood concentration of the apoptotic marker CK18 M30 and the number of TUNEL-positive cells in the liver of ketotic cows were 1.19- and 2.61-fold, respectively, higher than the values observed in control cows. Besides, Caspase 3 activity was significantly increased in the liver of ketosis cows. Importantly, the levels of phosphorylated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) were significantly increased but the level of phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) was markedly decreased, which further promoted tumor protein 53 (p53) expression and inhibited nuclear factor E2-related factor 2 (Nrf2) expression. The apoptosis-related molecules p21, MDM2, Caspase 3, Caspase 9 and Bax were expressed at significantly higher levels in ketotic cows than in healthy cows, whereas the anti-apoptosis molecule Bcl-2 was expressed at significantly lower levels. Conclusions: Based on these results, ketotic cows display severe hepatic oxidative stress. The hepatic MAPK-p53-Nrf2 apoptotic pathway is over induced and partially mediated apoptotic damage in the liver.

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Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Cited by 81 publications

References 46 publications

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

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